Research Round-Up

Research Round-Up: Insights of the Year 2013-2014 (In Imaging and Biomarkers)

In our final issue for 2014, the HD Insights team wanted to recognize the most influential papers in HD research in the 2013–2014 year. Our staff, Editorial Board, and leading HD researchers nominated the eleven papers below in three categories: lab research, clinical research, and imaging and biomarkers. The HD Insights Editorial Board then voted to select the three most influential papers, one in each category. The authors of the winning papers will present their research in a panel discussion at the Huntington Study Group meeting on November 7, 2014. Congratulations to all the nominees and winners!

Metabolic network as a progression biomarker of premanifest Huntington’s disease

By: Tang CC, Feigin A, Ma Y, Habeck C, Paulsen JS, Leenders KL, Teune LK, van Oostrom JC, Guttman M, Dhawan V, Eidelberg D (Summary by Chris C. Tang, MD, PhD)

J Clin Invest. 2013 Sep 3; 123(9):4076-88. doi: 10.1172/JCI69411. Epub 2013 Aug 29.

image cThe need for sensitive and accurate measurements of preclinical disease progression in at-risk individuals has been a major roadblock in the development of effective treatment for neurodegenerative disorders. In this fluorodeoxyglucose positron emission tomography (FDG-PET) study, we used a novel computational approach to identify and validate a brain network biomarker of disease progression in premanifest HD carriers. The subjects, who underwent longitudinal metabolic imaging in the rest state, exhibited a significant linear increase in network activity over seven years, continuing even as clinical manifestations emerged. The progression rate of network activity in this cohort was nearly identical to that measured prospectively in an independent cohort of premanifest HD carriers scanned longitudinally over a 2.3 ± 0.3 – year period. Moreover, this rate was found to be faster than the corresponding rates of conventional single-region measurements (i.e. caudate D2 binding and tissue volume) acquired in the same subjects. Thus, the metabolic network can provide a sensitive and reliable means of assessing systems-level changes in the progression of premanifest HD. This network biomarker is currently undergoing further validation in a multicenter longitudinal trial as part of the PREDICT-HD study. The results will help determine its utility in future clinical trials on new treatments targeted at slowing the progression of HD in the premanifest period.

Clinical and biomarker changes in premanifest Huntington disease show trial feasibility: A decade of the PREDICT-HD study

By: Paulsen JS, Long JD, Johnson HJ, Aylward EH, Ross CA, Williams JK, Nance MA, Erwin CJ, Westervelt HJ, Harrington DL, Bockholt HJ, Zhang Y, McCusker EA, Chiu EM, Panegyres PK; PREDICT-HD Investigators and Coordinators of the Huntington Study Group (Summary by Christina Colletta, BA)

Front Aging Neurosci. 2014; 6: 78. Published online Apr 22, 2014. doi:10.3389/fnagi.2014.00078

image dClinical trials to test novel therapies in individuals with premanifest HD have been limited by the scarcity of proven outcome measures and objective measures of disease progression. PREDICT-HD, a thirteen year study, aims to identify markers of HD-related change in individuals with premanifest and early HD needed to determine whether HD treatments are effective early in the disease process. This year’s analysis of the PREDICT-HD data found changes occurring in 36 of 39 potential outcome measures examined over a ten year period in individuals with premanifest HD, which could potentially be used as outcome measures in future therapeutic trials. Specifically, outcome measures of imaging based on regional brain volumes had the largest effect sizes. A motor assessment showed the next highest effect size, followed by a cognitive assessment of working memory, complex scanning and processing speed. Measures of function related to health and disability and measures of psychiatric symptoms such as obsessive-compulsive disorder were also found to show significant change over time. Using these and other outcome measures, clinical trials could be initiated seven to twelve years before motor diagnosis.


HTRF analysis of soluble huntingtin in PHAROS PBMCs

By: Moscovitch-Lopatin M, Goodman RE, Eberly S, Ritch JJ, Rosas HD, Matson S, Matson W, Oakes D, Young AB, Shoulson I, Hersch SM; Huntington Study Group PHAROS Investigators (Summary by Steven M. Hersch, MD, PhD and Miriam Moscovitch-Lopatin, PhD, PMP)

Neurology. 2013 Sep 24; 81(13):1134-40. doi: 10.1212/WNL.0b013e3182a55ede. Epub 2013 Aug 21.

image fMutant huntingtin (mHTT) is a target of many treatments currently being developed for HD. Therefore, the ability to measure levels of mHTT in humans will be crucial to future research efforts. Measuring mHTT has been very technically challenging. In our study of white blood cell samples from the PHAROS study, we used a sophisticated fluorescent assay to detect higher relative values of soluble mHTT in gene carriers (CAG≥37) prior to symptoms, and relatively lower values in symptomatic HD subjects.

The study demonstrated that soluble mHTT can be usefully detected in blood, and that HD may influence its levels. Since then, we have used this same assay in blood from early HD subjects participating in the HSG’s Reach2HD trial of PBT2 (PRANA Biotechnology), and found that the treatment can affect soluble mHTT levels. Currently, we are developing an assay that can also measure mHTT aggregates in clinical samples, which we believe will also prove useful for developing treatments that target huntingtin.


Multi-modal neuroimaging in premanifest and early Huntington’s disease: 18 month longitudinal data from the IMAGE-HD study

By: Domínguez D JF, Egan GF, Gray MA, Poudel GR, Churchyard A, Chua P, Stout JC, Georgiou-Karistianis N (Summary by Nellie Georgiou-Karistianis, PhD)

PLoS ONE. 2013 Sep 16; 8(9):e74131. doi: 10.1371/journal.pone.0074131.

IMAGE-HD is an Australia-based longitudinal multimodal biomarker development study that followed individuals with HD, and healthy controls, over 30 months. Results from IMAGE-HD have made significant contributions to biomarker discovery and to understanding of the impact of HD neuropathology on brain structure, microstructure, connectivity, and function during both the premanifest and early symptomatic stages.

However, much remains to be discovered about the contribution of specific brain regions and/or networks to the phenotypic heterogeneity of HD, and whether these decline at different rates. Such knowledge will be essential for well-targeted disease management strategies and therapeutic interventions. It will be important in the future to investigate the heterogeneity of HD in terms of brain endophenotypes and their relationships with cognitive, psychiatric and motor exophenotypes. Understanding how genetic and/or environmental factors modify these relationships and influence their development will be key to this endeavor. This will require a range of innovative approaches and novel analytical techniques, such as high throughput connectomics and predictive computational models.

Image: The Monash CAVE2™, next-generation immersive hybrid 2D and 3D virtual reality environment that enables the interactive exploration of high-throughput imaging data to develop new hypotheses and discover new biomarkers.

Image: The Monash CAVE2™, next-generation immersive hybrid 2D and 3D virtual reality environment that enables the interactive exploration of high-throughput imaging data to develop new hypotheses and discover new biomarkers.

There is also growing evidence for the potential benefit of cognitive and physical training in forestalling further worsening of HD symptoms. Such non-pharmaceutical interventions offer new and exciting possibilities to explore disease-modifying potential and to determine their neural mechanisms of action.

The new CAVE2™ at Monash University will provide state-of-the art capacity for high-throughput neuroimaging data for visualization and sorting of brain images based on pre-defined characteristics, which will enable imaging data to be visualized in new and exciting ways.

Research Round-Up

By: Lise Munsie, PhD

In the clinic…

clinicThe globus pallidus (GP) is thought to be involved in cognitive processes controlling actions, and thus is a possible target for deep brain stimulation (DBS) in HD patients. Beste and colleagues1 report a case control study of patients who received GPDBS, and measured patients’ error monitoring processing, an output mediated by the basal ganglia known to be altered in HD. The preliminary results suggest that the GP-DBS is safe in this population and yields positive results with respect to cognitive function.

In the past decade, transplantation of fetal striatal tissue into HD patients has emerged as an experimental treatment; however, recent evidence suggests that mutant huntingtin (mHTT) has the ability to spread between cells. Cicchetti and colleagues2 examined intracerebral allografts transplanted into patients approximately one decade ago, who subsequently died secondary to HD progression. The results showed mHTT aggregates in the extracellular matrix of the donor tissue, suggesting that mHTT has the ability to spread, and supporting non-cell autonomous effects of mHTT. How mHTT spreads will be the subject of further study.

Finally, PREDICT-HD has released their report on a decade-long trial that uses longitudinal data from premanifest HD individuals, reporting on biomarker and clinical progression assessments.3 This work has documented 39 different variables, 36 of which show changes that can be measured between premanifest and control individuals, and will inform the design of future clinical trials for treatments aimed at individuals with premanifest HD.

In the neurons…

Huntingtin (HTT) has been shown to be functionally involved in aspects of axonal transport, and researchers are exploring axonal physiology and transport as functional targets for drug discovery in HD.

Smith and colleagues4 report on their new heterozygous knock-in mouse model of HD, which recapitulates motor deficits, inclusion formation and decreased striatal volume in HD. Synaptic, cytoskeletal and axonal transport proteins such as kinesin, dynein, and dynactin are altered in this mouse model prior to neurodegeneration, suggesting that the proteins may be a good target for pre-symptomatic drug discovery.

Marangoni and colleagues5 use HD mouse models crossed with YFP-H transgenic mice, which express the fluorescent marker protein YFP in a subset of neurons, to investigate axon pathology and examine axonal swelling in relation to HD progression. Interestingly, age-dependent axonal swelling was evident in a full-length homozygous knock-in HdhQ140 model, but not in the widely used transgenic hemizygous R6/2 model. This axonal swelling did not correlate with aggregate formation, indicating that soluble mHTT may affect axons and axonal transport.

Finally, Wong and Holzbaur6 report on HTT and HAP1 involvement in axonal transport of autophagasomes in LC3-GFPmice. By live-cell imaging they demonstrate that mHTT causes a defect in axonal autophagasome transport, leading to inefficient degradative functions. The role of HTT and HAP1 in axonal transport seems to be mediated by binding to motor axonal proteins such as dynein, kinesin, and dynactin. This decreased degradative capacity leads to an increase in accumulation of mitochondrial fragments.

In the genes…

genesGene knockdown and silencing are powerful tools for scientific discovery and leading possibilities for HD therapy. In a recent Nature Medicine report,7 Wang and colleagues describe their use of the crerecombinase system to selectively knock down mutant huntingtin (mHTT) in brain specific regions in a full-length, floxed-exon1 BACHD mouse model. They found that lowering mHTT in striatal neurons alone does not ameliorate all phenotypes, and that cortical knockdown of mHTT has consequences for striatal synaptic pathologies. This confirms the non-cell autonomous role of HTT and shows that HTT-lowering strategies in multiple brain regions will be needed.

Drouet and colleagues8 examined the use of short hairpin RNA (shRNA) targeting single nucleotide polymorphisms (SNPs) specific to the mHTT allele. Their shRNA platform that targets SNPs in exons 39, 50, 60 and 67 is effective in silencing gene expression in lentiviral rodent models, BACHD mice, and neural stem cells derived from HD patient embryonic stem cells. Importantly, in cells with glutamine repeats of 44, brain-derived neurotrophic factor (BDNF) axonal trafficking is impaired. When these cells are treated with allele-specific shRNA, BDNF vesicular trafficking improves.Hu and colleagues9 report on the optimization of single-stranded silencing RNAs (ss-siRNA). The report describes modifying the ss-siRNA length, chemistry, lipid conjugation and structure by introducing mismatches. They found that certain ss-siRNAs with optimized mismatched bases relative to the expanded CAG tract were potent inhibitors of mHTT, both in vivo and in the HdhQ175 knock-in mouse model, as well as silencing a Q47 allele in patient-derived fibroblasts.


1 Beste C, Mückschel M, Elben S, J Hartmann, et al. Behavioral and neurophysiological evidence for the enhancement of cognitive control under dorsal pallidal deep brain stimulation in Huntington’s disease. Brain Struct Funct. 2014 May 31. [Epub ahead of print] PubMed ID: 24878825.

2 Cicchetti F, Lacroix S, Cisbani G, Vallières N, et al. Mutant huntingtin is present in neuronal grafts in huntington disease patients. Ann Neurol. 2014 May 6. doi: 10.1002/ana.24174. [Epub ahead of print].

3 Paulsen JS, Long JD, Johnson HJ, Aylward EA, et al. Clinical and biomarker changes in premanifest Huntington disease show trial feasibility: A decade of the PREDICT-HD study. Front Aging Neurosci. 2014;6:78. Prepublished online Mar 13, 2014. doi: 10.3389/ fnagi.2014.00078.0081528.

4 Smith GA, Rocha EM, McLean JR, Hayes MA, et al. Progressive axonal transport and synaptic protein changes correlate with behavioral and neuropathological abnormalities in the heterozygous Q175 KI mouse model of Huntington’s disease. Hum Mol Genet. 2014 Apr 30. [Epub ahead of print].

5 Marangoni, M. et al. Age-related axonal swellings precede other neuropathological hallmarks in a knock-in mouse model of Huntington’s disease. Neurobiol Aging. 2014 Oct; 35(10):2382-2393. doi:10.1016/j.neurobiolaging.2014.04.024.

6 Wong YC, Holzbaur EL. The regulation of autophagasome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J Neurosci. 2014 Jan 22; 34(4):1293-305. doi: 10.1523/JNEUROSCI.1870-13.2014.

7 Wang N, Gray M, Lu X-H, Cantle JP, et al. Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington’s disease. Nat Med. 2014 28 Apr;20:536-541.

8 Drouet V, Ruiz M, Zala D, Feveux M, et al. Allele-specific silencing of mutant huntingtin in rodent brain and human stem cells. PLoS One. 2014 Jun 13; 9(6):e99341. doi: 10.1371/journal.pone.0099341. eCollection 2014.

9 Hu J, Liu J, Yu D, Aiba Y, et al. Exploring the effect of sequence length and composition on allele-selective inhibition of human huntingtin expression by single-stranded silencing RNAs. Nucleic Acid Ther. 2014 Jun; 24(3):199-209. doi: 10.1089/nat. 2013.0476. Epub 2014 Apr 2

Research Round-Up

By: Lise Munsie, PhD

In cell biology…

The exact molecular mechanism of the huntingtin (Htt) protein is largely unknown. A paper from Dr. Solomon Snyder’s lab at Johns Hopkins that probes the link between Htt and the striatal-specific protein Rhes was recently published in the Journal of Biological Chemistry.1 This paper implicates Rhes in mTOR-independent autophagy, and demonstrates that binding of mutant Htt (mHtt) with Rhes inhibits the autophagic function of Rhes in a PC12 cell model. Autophagy becomes more important in aging cells; therefore, alterations to Rhes in HD could explain striatal-specific degeneration, as well as the late-onset characteristics of HD.

Transcriptional dysregulation is another known factor in the progression of HD. A recent report in Human Molecular Genetics from McFarland and colleagues describes the binding of Htt to the transcription factor MeCP2, using fluorescence lifetime imaging to measure Förster resonance energy transfer (FLIM-FRET).2 This report indicates that Htt binds to MeCP2, primarily in the nucleus. Binding of MeCP2 with Htt is enhanced in the presence of mHtt and may be involved in the change in BDNF levels that are characteristic of HD.

Another major theme in HD pathology is energetic defects due to mitochondrial dysfunction. Gouarné and colleagues report on mitochondrial respiratory function in different neuronal populations in a rat model of HD in their recent paper published in PLOS ONE.3 The oxygen consumption rate and extracellular acidification rate were reduced in striatal neurons, but not in cortical neurons in the presence of physiological factors, indicating a specific defect in glycolysis in the striatal neurons.

1 Mealer RG, Murray AJ, Shahani N, et al. Rhes, a striatal-selective protein implicated in Huntington disease, binds Beclin-1 and activates autophagy. J Biol Chem. 2013 Dec 9;doi:10.1074/jbc.M113.536912jbc.M113.536912.

2 McFarland KN, Huizenga MN, Darnell SB, et al. MeCP2: a novel Huntingtin interactor. Hum Mol Genet. 2013 Oct 18;doi: 10.1093/hmg/ddt499.

3 Gouarné C, Tardif G, Tracz J, et al. Early deficits in glycolysis are specific to striatal neurons from a rat model of Huntington disease. PLOS ONE. 2013 Nov 26; 8(11): e81528. doi:10.1371/journal.pone. 0081528.

In pharmaceuticals…

pharmTetrabenazine (TBZ), a catecholaminedepleting agent first used for the treatment of schizophrenia, has great efficacy in hyperkinetic movement disorders. However, its mechanism of action remains incompletely understood. TBZ noncompetitively inhibits VMAT2, and Ugolev and colleagues recently uncovered additional mechanisms involved in the compound’s interaction with VMAT2.1 Using directed evolution and mutant isolation in yeast, the group found conserved glycine and proline residues that are required for TBZ binding, and found that the binding site for TBZ is distinct from the substrate binding site on VMAT2.

TBZ can cause parkinsonian symptoms due to a decrease in dopamine D2 Receptor transmission. A report by Podurgiel and colleagues in Neuroscience looks at tremulous jaw movements in rats, which are mimetic of parkinsonian tremor. The report aims to determine whether A2a antagonists could attenuate tremulous jaw movements induced by TBZ.2 The researchers found that MS3-X or A2a knockout attenuates tremulous jaw movements; therefore, an A2a inhibitor could be used in concert with TBZ as an anti-parkinsonian drug.

Shen and colleagues examined the long-term safety and efficacy of TBZ in an observational open-label study of 145 patients who were followed for one to 11 years. Patient response to TBZ did not vary based on the severity of chorea nor concomitant drug use. The most common adverse events reported were somnolence, insomnia, depression, accidental injury, and dysphagia. The study concluded that TBZ is nevertheless safe and effective for the treatment of chorea in HD patients.3

1 Ugolev Y, Segal T, Yaffe D, et al. Identification of conformationally sensitive residues essential for inhibition of vesicular monoamine transport by the noncompetitive inhibitor tetrabenazine. J Biol Chem. 2013 Sep 23; 288:32160-32171.

2 Podurgiel SJ, Nunes EJ, Yohn SE, et al. The vesicular monoamine transporter (VMAT-2) inhibitor tetrabenazine induces tremulous jaw movements in rodents: implications for pharmacological models of parkinsonian tremor. Neurosci. 2013 Oct 10;(250): 507-519.

3 Shen V, Clarence-Smith K, Hunter C, Jankovic, J. Safety and efficacy of tetrabenazine and use of concomitant medications during long-term, open-label treatment of chorea associated with Huntington’s and other diseases. Tremor Other Hyperkinet Mov. 2013 Oct 22; 3. pii: tre-03-191-4337-1.

In neuroscience…

brainHuntingtin (Htt) has important effects on the specific properties of nerve cells. Xu and colleagues designed an elegant mouse model that selectively expresses exon1 mutant Htt (mHtt) in synaptic terminals, achieved by tagging mHtt to SNAP25.1 Their results show that this model has age-dependent neurological symptoms of HD, and alterations in synaptic transmission. They also show that Htt can bind the polyproline-rich regions of synapsin-1. Alterations to this binding by mHtt may be responsible for pre-synaptic defects.

A recent paper published by Parsons and colleagues finds a presynaptic role of wildtype Htt.2 In the YAC18 mouse model there is an increase in the amount of synaptic PSD95, and the size of the PSD95 clusters in medium spiny neurons cocultured with cortical neurons. This effect was observed in medium spiny neurons even when only the cortical neurons were over-expressing Htt, indicating a presynaptic effect leading to alterations in PSD95. This increase in PSD95 clustering occurs concomitant with an increase in palmitoylation of PSD95, and requires the actions of brain-derived neurotrophic factor. Consequently, the effects of Htt on synaptic architecture need to be further studied, because Htt knockdown is currently a promising pharmacological approach for treatment of HD.

Finally, Wojtowicz and colleagues examine astrocytes, a currently understudied part of neuronal circuitry with respect to HD. They found that the release of nonsynaptic GABA from depolarized astrocytes, by the action of GAT-3, is strongly reduced in HD mice.3 This suggests that regulating GAT-3 may be a therapeutic target for HD symptoms.

1 Xu Q, Huang S, Song M, et al. Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms. J Cell Biol. 2013 Sep 30;202(7):1123-1138.

2 Parsons MP, Kang R, Buren C, et al. Bidirectional control of postsynaptic density-95 (PSD-95) clustering by huntingtin. J Biol Chem. 2013 Dec 17; doi: 10.1074/jbc.M113.513945jbc.M113.513945.

3 Wojtowicz AM, Dvorzhak A, Semtner M, Grantyn R. Reduced tonic inhibition in striatal output neurons from Huntington mice due to loss of astrocytic GABA release through GAT-3. Front Neural Circuits. 2013 Nov 26; 7:188. doi: 10.3389/fncir.2013.00188.

Research Round-Up

By: Lise Munsie, PhD

In the lab…

Caron and colleagues describe properties of the huntingtin protein based on sensitive fluorescent sensors and using Förster resonance energy transfer (FRET) 1. They describe the intramolecular proximity between the domains flanking the polyglutamine tract, the N-terminus of huntingtin, and the polyproline region. Pathogenic CAG repeat lengths alter the ability of huntingtin to fold, and to interact with itself and other proteins. This may be part of the mechanism of disease, and the FRET assay may act as a read-out for altered huntingtin function. An early event in HD pathogenesis is activation of caspase-6 in the central nervous system. Ehrnhoefer and colleagues explored the role of caspase-6 in peripheral phenotypes such as the muscle wasting observed in HD2. They found that activity of p53, a transcriptional activator of caspase-6, is increased in neuronal and peripheral tissues of HD patients and mouse models of HD, leading to the activation of caspase-6. This implies that peripheral dysfunction in HD may stem from the same pathways that cause neurodegeneration. Murmu and colleagues examined the kinetics of dendritic spine alterations and synaptic plasticity in the R6/2 mouse model of HD, using long-term two-photon imaging through a cranial window3. By tracking individual dendrites and spines over six weeks, they show that a decrease in spine density and survival is associated with disease progression, and is evident before behavioral change and neuronal loss. In the mouse model there is increased spine turnover, and newly formed spines are less likely to mature. Future therapies should examine ways to stabilize dendritic spines and modulate spine turnover.

In the scanner…

round upThe Australia-based IMAGE-HD group is using MRI imaging to investigate functional changes in the macro and microstructure of HD brains over time. Their recent study published in PloS ONE used a 3T MRI scanner to observe differences in premanifest and early symptomatic HD patients4. Longitudinal change in caudate volume discriminates between groups at all stages of the disease. Caudate atrophy is present before onset of symptoms and is one of the most sensitive measures that may work as a biomarker. Recent data suggests that changes in HD brains extend to the white matter tract. A second study published in PLoS ONE used diffusion tensor imaging (DTI) and tractography to investigate mechanisms that underlie regional specific changes in white matter during the course of HD5. This study focused on the corpus callosum, associating changes in subregions of this structure with motor and cognitive outputs. The study found that demylenation and axon damage is likely to occur before onset of HD symptoms, and that abnormal structural connectivity is associated with HD progression and the number of CAG repeats. Neurovascular abnormalities are increasingly shown to have connections with neurodegenerative diseases such as HD. Lin and colleagues report on a novel fMRI technique called 3-dimensional microscopic magnetic resonance angiography, and their use of this technique to assess neurovascular changes in the R6/2 mouse model of HD6. Their work showed that disease progression is associated with an increase in vessel volume function and cerebral blood volume. This data correlates with immunostaining of human tissues that looks at microvascular morphology. The paper suggests that these changes could be used as a biomarker for early diagnosis of HD.

In the clinic…

In a recent issue of Nature Genetics, Mason and colleagues describe a new therapeutic lead for HD7. Using a genomewide over-expression suppressor screen in yeast, the group defines genes that suppress cell toxicity that is induced by mutant huntingtin fragment expression. The paper focuses on genes that encode glutathione peroxidases (GPxs), which are antioxidant enzymes. These enzymes do not inhibit autophagy like many other antioxidants, and the group found that genetic or pharmacological manipulation of GPx can rescue many HD phenotypes in yeast, fly and mammalian models. GPx therapy shows promise, and well-tolerated GPx mimetics are readily available for trials. Another experimental antioxidant therapy was explored in a PLoS ONE article that looked at protective effects of glial conditioned medium (GCM) in the R6/1 mouse model of HD8. GCM is enriched with antioxidants and neurotrophic factors, and is hypothesized to have therapeutic effects. Perucho and colleagues infused GCM into the left striatum of R6/1 mice and found positive effects on cell survival and inclusion formation. Another group is looking at new ways to specifically target the cognitive deficits in HD. Saavedra and colleagues investigated the involvement of the neuronal nitric oxide synthase/3′,5′-cyclic guanosine monophosphate (nNOS/cGMP) hippocampal pathway in HD cognitive decline9. They found a decreased level of cGMP in the HD mouse hippocampus, and found that injecting sildenafil, a phosphodiesterase (PDE5) inhibitor that increases cGMP levels, leads to memory improvement. Targeting this pathway may slow cognitive decline in HD.


1 Caron NS, Desmond CR, Xia J, Truant R. Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin. Proc Natl Acad Sci USA. 2013 Jul 3; 110:14610-5.

2 Ehrnhoefer DE, Skotte NH, Ladha S, et al. P53 increases caspase-6 expression and activation in muscle tissue expressing mutant huntingtin. Hum Mol Genet. 2013 Sep 18; doi:10.1093/hmg/ddt458.

3 Murmu RP, Li W, Holtmaat A, Li JY. Dendritic spine instability leads to progressive neocortical spine loss in a mouse model of Huntington’s disease. J Neurosci. 2013 Aug 7; 33(32):12997-3009. doi: 10.1523/JNEUROSCI.5284-12.2013.

4 Domínguez D JF, Egan GF, Gray MA, et al. Multi-modal neuroimaging in premanifest and early Huntington’s disease: 18 month longitudinal data from the IMAGE-HD study. PLoS ONE. 2013 Sep 16;8(9):e74131. doi:10.1371/journal.pone.0074131.

5 Phillips O, Sanchez-Castaneda C, Elifani F, et al. Tractography of the corpus callosum in Huntington’s disease. PLoS ONE. 2013 Sep 3; 8(9):e73280. doi:10.1371/journal.pone.0073280.

6 Lin CY, Hsu YH, Lin MH, et al. Neurovascular abnormalities in humans and mice with Huntington’s disease. Exp. Neurol. 2013 Sep 10. pii: S0014-4886(13)00268-9. doi: 10.1016/j.expneurol. 2013.08.019. [Epub ahead of print].

7 Mason RP, Casu M, Butler N, et al. Glutathione peroxidase activity is neuroprotective in models of Huntington’s disease. Nat Genet. 2013 Oct ;45(10):1249-54.

8 Perucho J, Casarejos MJ, Gomez A, et al. Striatal infusion of glial conditioned medium diminishes Huntingtin pathology in R6/1 mice. PLoS ONE. 2013 Sep 13; 8(9):e73120. doi:10.1371/ journal.pone.0073120.

9 Saavedra A, Giralt A, Arumi H, et al. Regulation of hippocampal cGMP levels as a candidate to treat cognitive deficits in Huntington’s disease. PLoS ONE. 2013 Sep 5; 8(9):e73664. doi: 10.1371/journal.pone.0073664.

Research Round-Up

By: Lise Munsie, PhD

In the lab. . .

Cepeda and colleagues performed an electrophysiological study of the striatal microcircuit in HD mouse models to examine the cause of increased GABA synaptic activity in medium-sized spiny neurons1. Investigation of GABAergic microcircuits revealed that feedforward and feedback inhibition to medium-sized spiny neurons may be the cause of increased GABA activity in these models of HD.

Ben M’Barek and colleaproteingues described huntingtin (Htt) involvement in anxiety/ depression-like behaviors based on specific cyclin-dependent kinase 5 (Cdk5) phosphorylation sites on Htt at positions serine (S) 1181 and 12012. Investigators used mouse models with point-directed mutagenesis to demonstrate that Htt phosphorylated at S1181/1201 has a role in neurogenesis and affects anxiety and depression. The mechanism is likely to be increased axonal trafficking of brain-derived neurotrophic factor.

Borgonovo and colleagues studied Htt involvement in vesicular transport.3 Htt is involved in clathrin-mediated endocytosis (CME), which is required for the internalization of NMDA and AMPA receptors. Adaptor protein complex-2 (AP-2) is a protein involved in clathrin-coated vesicle biogenesis. The investigators found that AP-2 mislocalizes from membranes to cytosol in the brains of HD mice and cultured striatal cell lines. They also observed an overall decrease in CME with a transferrin uptake assay.

In the genes. . .

Biomarker and age at onset studies show patient-to-patient variation that is likely to be due to environmental and genetic modifying factors.

Kloster and colleagues investigated a possible link between regulation of the cannabinoid receptor 1 (CNR1) gene and age at onset.4 CNR1 encodes type 1 cannabinoid receptors, which are down-regulated in the basal ganglia of individuals with HD and are thought to play a role in HD pathogenesis. In a study of 473 individuals with HD, the investigators found a significant association between age at onset and the length of ATT repeat polymorphisms in CNR1. They further define a single-nucleotide polymorphism (SNP) in the 3’ UTR, which may affect miRNA binding, is also associated with age at onset.

Berger and colleagues studied haplotypes associated with the gene OGG1, which encodes for a DNA repair enzyme potentially responsible for somatic expansion of CAG repeats. The investigators also studied the gene XPC, which encodes for a protein involved in cell cycle control, redox homeostasis, and the removal of oxidative DNA damage.5 They found two OGG1/XPC haplotypes were associated with age at onset independent of CAG repeat length, which may be another genetic modifier for HD.

Ramos and colleagues completed a study of polymorphisms in NMDA receptors and dopamine-related proteins such as transporters, which have been previously suggested to modify the course of HD. Results showed no significant association between HD pathogenesis or age at onset to previously presumed polymorphisms in genes such as GRIN2A or GRIN2B that affect glutamatergic pathways, or in genes such as DRDs or DAT1 that affect dopaminergic pathways.6


In clinical trials. . .

Extensive efforts have gone into defining the natural history of HD and identifying biomarkers for HD to inform the design of clinical trials and define trial outcomes.

Tabrizi and colleagues completed a 36-month longitudinal study (TRACK-HD) to assess clinical and biological markers of HD in individuals who were premanifest for HD, and individuals with early manifest HD.7 The results defined a range of motor, psychiatric, cognitive and imaging-based measures that can be used to evaluate and predict disease progression in individuals at varying stages of premanifest and manifest HD. Inter-tap interval testing and gray matter volume change were especially sensitive indicators and may have prognostic value.

Hua and colleagues recently completed a small pilot study investigating cerebral blood volume as a potential quantitative biomarker in individuals with prodromal HD.8 Functional brain changes in HD that lead to neuronal dysfunction may be preceded by a metabolic or neurovascular abnormality. Using a non-invasive MRI technique to observe arteriolar cerebral blood volume in cortical gray matter, investigators observed an increase in arteriolar blood volume in the frontal cortex among individuals with prodromal HD compared to age-matched controls.


1 Cepeda C, Galvan L, Holley SM, et al. Multiple sources of striatal inhibition are differentially affected in Huntington’s disease mouse models. J Neurosci. 2013; 33:7393-406.

2 Ben M’Barek K, Pla P, Orvoen S, et al. Huntingtin mediates anxiety/ depression-related behaviors and hippocampal neurogenesis. J Neurosci. 2013; 33: 8608-20.

3 Borgonovo JE, Troncoso M, Lucas JJ, Sosa MA. Mutant huntingtin affects endocytosis in striatal cells by altering the binding of AP-2 to membranes. Exp neurol. 2013 ;241:75-83.

4 Kloster E, Saft C, Epplen JT, Arning L. CNR1 variation is associated with the age at onset in Huntington disease. Eur J Med Genet. 2013;56(8):416-9.

5 Berger F, Vaslin L, Belin L, et al. The impact of single-nucleotide polymorphisms (SNPs) in OGG1 and XPC on the age at onset of Huntington disease. Mutat Res. 2013;755(2):115-9.

6 Ramos EM, Latourelle JC, Gillis T, et al. Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington’s disease motor onset. Neurogenetics. 2013.

7 Tabrizi SJ, Scahill RI, Owen G, et al. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol. 2013;12:637-49.

8 Hua J, Unschuld PG, Margolis RL, et al. Elevated arteriolar cerebral blood volume in prodromal Huntington’s disease. Mov Disord. 2013.

Research Round-Up

By: Lise Munsie, PhD

In the lab. . .

Future clinical treatments for HD are likely to vary from patient to patient and involve multiple therapies to address all symptoms of the disease. Investigators are seeking to find novel ways to assess HD pathology, and they continue to research the molecular mechanisms of HD.

in the labSathasivam and colleagues describe aberrant splicing of Htt that leads to mRNA translation of an Htt exon1 fragment in the presence of the expanded polyglutamine tract1 that is characteristic of mHtt. Their results suggest that mHtt may be present at exon1 as a result of direct translation, not proteolytic cleavage.

Steinert and colleagues used a drosophila larva neuromuscular junction model to investigate glutamatergic synaptic transmission in HD2. Their manuscript describes vesicle defects in the presence of exon1 mHtt and reports that an overexpression of Rab11 at the endosomal recycling system rescues both synaptic and behavioral defects in this model.

Previous work has implicated the Rhes protein with the progression of HD. Rhes protein is a GTP binding protein enriched in the striatum. Baiamonte and colleagues crossed Rhes knockout mice with the R6/1 HD mouse model to study the effects of Rhes on the progression of HD3. The cross resulted in a delay in the behavioral symptoms of HD.

Lu and Palacino created a human neuronal model of HD4. Overexpressed Htt exon1 fragments recapitulated disease by causing protein aggregation and neurodegeneration in a neuronal population derived from induced pluripotent stem cells. The authors’ results support previously published data that suggests that soluble mHtt is a main toxic species.

In transition. . .

Promising pre-clinical data has emerged in the field of HD research.

in transitionMethylene blue, previously tested in Alzheimer’s disease, shows therapeutic potential in HD and is being tested for efficacy in HD readouts by a group at the University of California, Irvine. Sontag and colleagues report that methylene blue can inhibit the in vitro aggregation of mHtt and can also lead to functional improvements in the drosophila and R6/2 mouse models of HD5.

Human samples acquired by the TRACK-HD study have been used to develop an assay that detects levels of Htt in peripheral immune cells. Weiss and colleagues report the use of time-resolved Förster resonance energy transfer to quantify both total Htt and mHtt levels6. The assay detects differences in mHtt levels in different leukocyte populations. This study also reports that mHtt levels in monocytes were associated with rates of caudate and whole brain atrophy and ventricular expansion. Sawiak and colleagues created a public database of their ex vivo brain imaging from cohorts of both R6/2 and YAC128 HD mouse models7. Almost 400 datasets containing structural data and tissue maps for each individual brain are available. As in vivo data is obtained it will be added to this free online resource. Datasets may be accessed at handle/1810/243361 and may be viewed using online freeware. Medical imaging is at the forefront of biomarker research in HD. The availability of large datasets will aid investigators to make correlations between mouse models of HD and human brain imaging being undertaken for studies in neurodegenerative disease.

In the clinic. . .

A variety of therapeutic approaches are entering clinical trials for HD.

The drug PBT2, developed by Prana Biotechnology Ltd, has shown to improve cognition in Alzheimer’s disease8 and is now also a clinical trial candidate for HD. PBT2 is an 8-hydroxyquinoline analog that has affinity for transition metals, and may be able to liberate metals that contribute to pathology in HD. In a recent PloS One publication9, investigators report the alleviation of symptoms in a Caenorhabditis elegans model of aggregation, and the improvement of motor symptoms and a decrease in striatal atrophy in the R6/2 mouse model of HD, in response to PBT2. A phase II study of PBT2 for patients with early to mid-stage HD is ongoing10.

The ‘NEST-UK’ consortium at the University of Cambridge recently reported on the safety of using fetal striatal cell transplants to repair damaged cells in the striatum of HD patients11. Transplants were performed in five patients with mild HD symptoms and postoperative follow-up continued for up to 10 years. This follow-up was unable to detect any significant changes in either the Unified Huntington’s Disease Rating Scale or the Mini-Mental State Examination. However, this study does prove the safety of the protocol and lays the foundation for larger-scale studies of this intervention. Case reports have also featured the benefits and side effects of deep brain stimulation for HD12. Deep brain stimulation has been moderately successful for HD motor symptoms and has been shown to be safe for HD patients.


1 Sathasivam K, Neueder A, Gipson TA, et al. Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proceedings of the National Academy of Sciences of the United States of America 2013 Feb; 110(6):2366-70.

2 Steinert JR, Campesan S, Richards P, et al. Rab11 rescues synaptic dysfunction and behavioural deficits in a Drosophila model of Huntington’s disease. Human molecular genetics 2012 Jul; 21(13): 2912-22.

3 Baiamonte BA, Lee FA, Brewer ST, et al. Attenuation of Rhes activity significantly delays the appearance of behavioral symptoms in a mouse model of Huntington’s disease. PloS one 2013; 8(1):e53606.

4 Lu B, Palacino J. A novel human embryonic stem cell-derived Huntington’s disease neuronal model exhibits mutant huntingtin (mHTT) aggregates and soluble mHTT-dependent neurodegeneration. FASEB journal 2013 Jan.

5 Sontag EM, Lotz GP, Agrawal N, et al. Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington’s disease models. The Journal of Neuroscience 2012 Aug; 32(32):11109-19.

6 Weiss A, Trager U, Wild EJ, et al. Mutant huntingtin fragmentation in immune cells tracks Huntington’s disease progression. The Journal of Clinical Investigation 2012 Oct; 122(10): 3731-6.

7 Sawiak SJ, Wood NI, Carpenter TA, Morton AJ. Huntington’s disease mouse models online: high-resolution MRI images with stereotaxic templates for computational neuroanatomy. PloS one 2012; 7(12):e53361.

8 Faux NG, Ritchie CW, Gunn A, et al. PBT2 rapidly improves cognition in Alzheimer’s Disease: additional phase II analyses. J Alzheimers Dis 2010;20(2):509-16.

9 Cherny RA, Ayton S, Finkelstein DI, et al. PBT2 Reduces toxicity in a C. elegans model of polyQ aggregation and extends lifespan, reduces striatal atrophy and improves motor performance in the R6/2 mouse model of Huntington’s disease. J Huntington’s Dis 2012;1(2):211-9.

10 term=reach2hd&rank=1

11 Barker RA, Mason SL, Harrower TP, et al. The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington’s disease. J Neurol Neurosurg Psychiatry 2013 Jan.

12 Velez-Lago FM, Thompson A, Oyama G, et al. Differential and better response to deep brain stimulation of chorea compared to dystonia in Huntington’s disease. Stereotact Funct Neurosurg 2013 Jan; 91(2):129-33.

Research Round-Up

By: Lise Munsie, PhD

In the beginning…

In the past year, researchers have published on the use of stem cells to model Huntington disease (HD) and on investigations of stem cell use as a treatment for HD.

Sadan and colleagues1 induced mesenchymal stem cells into neurotrophic factor– secreting (NTF) cells, then transplanted the NTF cells into rats that had striatal lesions induced by quinolinic acid (QA). The NTF cells, whether derived from an HD patient or a control, survived transplantation and maintained an NTF-secreting phenotype leading to improved striatal volume and behavioural phenotypes.

Ma and colleagues2 showed that human embryonic stem cells can be directed into an enriched population of GABA medium spiny neurons. When GABA neurons were implanted into the striatum of a QA lesion mouse model, they maintained functionality, leading to phenotypic improvements in the mice.

An and colleagues3 corrected the genetic mutation in HD patient–derived induced pluripotent stem cell (iPSC) lines using homologous recombination, and found this also corrected many of the aberrant phenotypes associated with neural stem cells (NSC) derived from these iPSC lines. Genetically corrected NSCs were able to populate the striatum of the R6/2 mouse post-transplantation. Patient-specific cell replacement therapy with corrected mutant huntingtin (mHTT) CAG lengths may be feasible in the future.

The HD iPSC consortium4 generated and studied 14 iPSC lines from HD patients and controls. Investigators in different labs found clear and reproducible phenotypes associated with the disease-causing mutation, consistent in multiple lineages. These cell lines may be used in future assay development and screening in HD drug discovery efforts.

In the lab…

There is a vast breadth of recently published basic research in HD.

Dong and colleagues5 recently identified additional post-translational modifications in huntingtin. They coupled tandem affinity purification and 2D nano-LC mass spectrometry and found novel phosphorylation sites at serines 431 and 432. Phosphorylation at these sites was specific to polyglutamine-expanded huntingtin when N-terminal fragments were overexpressed in 293 cells. Milnerwood and colleagues6 developed a new protocol for studying excitatory transmission onto GABAergic medium spiny neurons, with specific focus on the effects of mutant huntingtin on the cortico-striatal pathway. Using striatal and cortical co-cultures, NMDAR-induced cell death increased in cultures derived from YAC128 mice. The researchers further showed this is associated with the misregulation of phosphorylated cAMP response element binding protein (CREB) leading to decreased transcription of pro-survival factors. The dysfunction was significantly reduced using specific NMDAR subunit inhibitors. Kordasiewicz and colleagues7 used transiently administered antisense oligonucleotides (ASOs), designed to suppress the expression of huntingtin, in HD mouse models and in non-human primates. In mouse models, ASOs were administered into the lateral ventricle and led to specific knockdown of the mHtt transgene and some phenotypic reversal. The knockdown was sustained in both animal models for up to three months post treatment, suggesting that ASOs may provide a clinically relevant strategy for combating HD.

In the clinic…

Important studies reviewing and analyzing previously obtained clinical data give new insights into disease mechanisms and assess current treatments for HD.

 Ji and colleagues8 conducted a population-based study assessing the incidence of cancer in Swedish patients with HD and other neurological diseases. The standardized incidence of cancer was significantly lower in patients with polyglutamine disease. The largest difference (0.47) was associated with HD gene carriers. Polyglutamine disease seems to be protective against benign and metastatic cancer.

Armstrong and Miyasaki9 looked at the data available for current pharmacological options for treating chorea. Their analysis showed that tetrabenazine, the only drug approved by the FDA specifically for the treatment of chorea, remains the best performing drug at a dose of 100 mg/day. Amantadine and rizuole give modest benefit. It is important to have multiple effective drugs available for HD patients due to tetrabenazine’s potential adverse effects and the necessary close monitoring of patients who receive the drug.

Unschuld and colleagues10 examined brain metabolite alterations, using magnetic resonance spectroscopy, in prodromal HD gene carriers with no gross brain morphological changes, and compared the metabolite alterations to controls. Eleven metabolites had decreases in Nacetyl aspartate and glutamate levels associated with prodromal HD. Future studies are needed to determine the utility of these results as longitudinal biomarkers for HD disease progression.


1 Sadan O, Shemesh N, Barzilay R, et al. Mesenchymal stem cells induced to secrete neurotrophic factors attenuate quinolinic acid toxicity: a potential therapy for Huntington’s disease. Experimental neurology. 2012 Apr;234(2):417-27.

2 Ma L, Hu B, Liu Y, et al. Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acidlesioned mice. Cell stem cell. 2012 Apr;10(4):455-64.

3 An MC, Zhang N, Scott G, et al. Genetic correction of Huntington’s disease phenotypes in induced pluripotent stem cells. Cell stem cell. 2012 Aug;11(2):253-63.

4 ThHD iPSC induced pluripotent stem cells from patients with Huntington’s disease show CAG-repeat-expansion-associated phenotypes. Cell stem cell 2012 Aug;11(2):264-78

5 Dong G, Callegari E, Gloeckner CJ, et al. Mass spectrometric identification of novel posttranslational modification sites in Huntingtin. Proteomics. 2012 Jun;12(12):2060-4.

6 Milnerwood AJ, Kaufman AM, Sepers MD, et al. Mitigation of augmented extrasynaptic NMDAR signaling and apoptosis in cortico-striatal co-cultures from Huntington’s disease mice. Neurobiol Dis. 2012 Oct;48(1):40-51.

7 Kordasiewicz HB, Stanek LM, Wancewicz EV, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron. 2012 Jun; 74(6):1031-44.

8 Ji J, Sundquist K, Sundquist J. Cancer incidence in patients with polyglutamine diseases: a population-based study in Sweden. Lancet Oncol. 2012 Jun;13(6):642-8.

9 Armstrong MJ, Miyasaki JM. Evidence-based guideline: Pharmacologic treatment of chorea in Huntington disease: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology2012 Aug 7;79(6):597-603.

10 Unschuld PG, Edden RA, Carass A, et al. Brain metabolite alterations and cognitive dysfunction in early Huntington’s disease. Movement Disorders. 2012 Jun;27(7):895-902.

Research Round-Up

By: Lise Munsie and Mahmoud Pouladi, PhD

In the scanner…

Huntington disease (HD) imaging data is providing new insights into the mechanism of disease, and is also providing sensitive biomarkers. Identification of biomarkers is critical to the success of clinical trials of disease-modifying therapeutic agents. Imaging techniques include magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and functional MRI (fMRI). The TRACK-HD team led by Prof. Sarah Tabrizi has now published its 24-month data, which supports the 12-month data from the team’s previous report, showing that imaging markers are the most effective method to detect disease-related group differences in premanifest and early HD patient groups.1 The team’s data also indicates that striatal and total white matter atrophy are the most sensitive anatomical measures of premanifest HD. Di Paola and colleagues used MRI to investigate changes in the corpus callosum, which has the largest white matter tract in the human brain.2 Their findings complement those of the TRACK-HD study; white matter changes in the corpus callosum in premanifest and early HD suggest that the corpus callosum may be a key structure in the development of the neuropathology of HD. MRI-observable changes in corpus callosum white matter may be a biomarker in the progression of HD. Zacharoff and colleagues published data on the R6/2 mouse model of HD.3 They used MRS to investigate changes in brain metabolites, and MRI to assess changes in brain volume. They found that changes in brain metabolites manifest before changes in brain volume. This data aids in validating HD mouse models for use in drug discovery and target design.

 In the lab…

Two studies in the December 2011 issue of Nature highlight Sirt1, an NAD-dependent protein deacetylase implicated in the regulation of cellular metabolism, as a potential therapeutic target for HD.

Jiang and colleagues demonstrated that mutant huntingtin (mHTT) inhibits Sirt1 deacetylase activity, which alters the acetylation status of a number of its substrates such as FoxO3a, and influences their function.4 Knockdown of Sirt1 in vitro exacerbated mHTT-mediated toxicity, whereas overexpression of Sirt1 restored the concentrations of acetylated FoxO3a and p53 to baseline levels and protected against mHTT toxicity. The authors reported that in N171-82Q and BACHD mice, overexpression of Sirt1 improved motor function and reduced neuropathology, including striatal and cortical atrophy. In N171-82Q mice some metabolic parameters were improved, including improved insulin sensitivity as shown by attenuated hyperglycaemia and decreased plasma insulin levels; improved glucose tolerance; and attenuated body weight loss. Jeong and colleagues examined the effect of modulation of Sirt1 levels in R6/2 mice.5 Brainspecific knockdown of Sirt1 worsened motor dysfunction and exacerbated striatal atrophy. Conversely, global overexpression of Sirt1 attenuated striatal atrophy and was associated with restoration of BDNF levels. Although there is a disconnect in the impact of Sirt1 overexpression on survival, body weight, and mHTT aggregates in the N171-82Q and R6/2 mice, these studies highlight a role for Sirt1 in the pathogenesis of HD. The neuroprotective effects of Sirt1 show that it is a potential therapeutic target for HD.

In the clinic…

Neuropsychiatric disturbances are common in HD patients, and two recent studies explore depression and apathy. Richards and colleagues exploited the richness of the data repository assembled as part of the European Huntington’s Disease Network REGISTRY Study, to examine the discriminant value of items on two depression rating scales, namely the Beck Depression Inventory (BDI), and the Hamilton Rating Scale for Depression (HAM-D).6 Using a discriminant analysis method, the authors found that items from the BDI were more likely than items from the HAM-D to discriminate depressed mood HD patients from those without depressed mood. Loss of interest, guilt, and suicidal thoughts were the best discriminators of depressed mood. Weight loss, measures of sleep disturbances, and irritability were poor discriminators of depressed mood. This study can assist in the development of refined measures of depression in HD patients. Reedeker and colleagues examined the incidence, course and predictors of apathy in HD in a prospective study.7 Patients were assessed using a modified version of the Apathy Evaluation Scale at baseline, and re-assessed after two years. Of the patients who completed the study, 14% who were free of apathy at baseline later developed apathy. The development of apathy in these patients was associated with a lower baseline Mini-Mental State Exam score, supporting a role for cognitive dysfunction in the development of apathy in HD. Of 34 patients with apathy at baseline, 14 subjects were no longer apathetic at follow-up, indicating that apathy in HD is reversible, and suggesting that targeting treatable causes of apathy may aid in combating apathy in HD.


1 Tabrizi SJ, Reilman R, Roos RAC, et al. Potential endpoints for clinical trials in premanifest and early Huntington’s disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurol. 2012; 11(1): 42-53.

2 Di Paola M, Luders E, Cherubini A, et al. Multimodal MRI analysis of the corpus callosum reveals white matter differences in presymptomatic and early Huntington’s disease. Cerebral Cortex. 2012 Jan 5 [Epub] doi:10.1093/ cercor/bhr360

3 Zacharoff L, Tkac I, Song Q, et al. Cortical metabolites as biomarkers in the R6/2 model of Huntington’s disease. Journal of Cerebral Blood Flow & Metabolism. 2011 1-13.

4 Jiang M, Wang J, Fu J, et al. Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med. 2011 Dec 18; 18(1):153-8.

5 Jeong H, Cohen DE, Cui L, Supinski A, et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med. 2011 Dec 18; 18(1):159-65.

6 Rickards H, Souza JD, Crooks J, et al. Discriminant Analysis of Beck Depression Inventory and Hamilton Rating Scale for Depression in Huntington’s Disease. J Neuropsychiatry Clin Neurosci. 2011 Sep 1;23(4):399-402.

7 Reedeker N, Bouwens JA, van Duijn E, et al. Incidence, Course, and Predictors of Apathy in Huntington’s Disease: A Two-Year Prospective Study. J Neuropsychiatry Clin Neurosci. 2011 Sep 1; 23(4):434-41.

Research Round-Up

By: Lise Munsie

In the lab. . .

in the labBasic research into the biochemical pathways underlying the pathogenesis of HD continues, with the aim of targeting these pathways for drug delivery. PGC1α, which controls many aspects of oxidative metabolism, has been a focus of recent efforts. Martin and colleagues showed that an upstream activator of PGC1α may be involved in the characteristic downregulation of PGC1α in HD patient brain and muscle samples.2 They also used a transcriptional readout of an HD rat model to show that MSK1, a nuclear protein kinase with low striatal levels in HD patients, is responsible for PGC1α activation. When overexpressed, MSK1 can activate PGC1α, possibly through histone H3 phosphorylation, and lead to positive outcomes in the HD rat model. Taherzadeh-Fard and colleagues looked at genetic modifiers via single nucleotide polymorphisms (SNPs) in HD patients, and showed that downstream PGC1α transcription factors NRF-1 and TFAM are genetic modifiers of the age of clinical onset of HD.3 These data strongly support modulation of PGC1α activity as a potential therapeutic approach in HD. Labbadia and colleagues investigated the therapeutic potential of activating chaperones for HD.4 They used HSP990, a brain-penetrating HSP90 inhibitor that can be administered orally, and showed that while activating chaperones via the heat shock response is initially therapeutic, the heat shock response is gradually attenuated as disease progresses. The shut-down of the heat shock response seems to be linked to epigenetic modifications, and indicates that this approach, although potentially beneficial, may be more complicated than originally hoped.


In the scanner. . .

Basic resein the scannerarch and clinical research are bringing us closer to disease modifying treatments for Huntington disease, but sensitive biomarkers are needed to assess disease progression and the efficacy of new treatments. Neuroimaging has now come into the spotlight to assist with this task, and large-scale, multi-site longitudinal studies such as TRACK-HD and PREDICTHD have recently released neuroimaging study results. The TRACK-HD team led by Dr. Sarah Tabrizi in London used magnetic resonance imaging (MRI) data to investigate clinical, cognitive, oculomotor and neuropsychiatric indicators of HD.2 They saw progression in prodromal HD over a 12-month period, and found that brain imaging measurements were the strongest and most consistent measures when tracking disease progression. TRACK-HD’s data has established an association between MRI neuroimages and clinically meaningful measures of disease progression. Furthermore, the study provides baseline data to estimate the sample sizes required to detect meaningful treatment-mediated improvements in a clinical trial. The PREDICT-HD team led by Dr. Jane Paulsen reported that their MRI data indicate that increased CAG length is associated with more rapid progression of striatal atrophy.3 Diana Rosas and colleagues used MRI to investigate the possible correlation between age of onset and rate of brain atrophy.4 The study showed that individuals whose motor symptoms appeared before the age of 40 years had an increased rate of brain atrophy. The study also found that topological distribution of cortical thinning was highly dependent on the age of onset and not necessarily on the length of CAG repeats.


In the clinic. . .

in the clinicRecent efforts in drug discovery for HD have shifted to exploring different methods for silencing the allele that codes for mutant huntingtin. Allele-specific silencing using antisense oligonucleotides (ASOs) has been successful in non-brain-related disorders, and with recent advances in chemistry, pharmacology and drug delivery, the possibility of using ASOs to treat brain disorders is becoming more realistic. Recent clinical efforts have explored novel approaches to improve ASOs and have sought to develop ways to silence the allele that codes for mutant huntingtin, while sparing the normal allele. Gagnon and colleagues showed that ASOs with certain chemical modifications can specifically silence the allele that codes for mutant huntingtin, although the mechanism of this silencing remains unknown.2 Interestingly, these effects were protein and not transcript-dependent. Fiszer and colleagues used repeat-targeting RNA duplexes to discriminate between expanded and non-expanded alleles, and to mediate RNA-induced silencing complex (RISC) – dependent target silencing.3 They used a duplex of pure CUG/CAG repeat sequences to silence the allele that codes for mutant huntingtin, and they increased allele selectivity by introducing single or double C>U substitutions in an effort to modulate RISC activity. Chung and colleagues found that an overexpressed antisense strand at the HD locus (huntingtin antisense – HTTAS) has the ability to modulate huntingtin expression, its sense transcript counterpart.4 These results suggest that continued investigation of overexpressed antisense strands and their ability to decrease huntingtin expression should be pursued.


1 Martin E, Betuing S, Pagès C, et al. Mitogen and stress – activated protein kinase 1 – induced neuroprotection in Huntington’s disease: role on chromatin remodeling at the PGC-1-alpha promoter. Hum Mol Genet 2011;20(12):2422-34.

2 Taherzadeh-Fard E, Saft C, Akkad DA, et al. PGC1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease. Mol Neurodegener 2011; 6(1):32.

3 Labbadia J, Cunliffe H, Weiss A, et al. Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease. J Clin Invest 2011; 121(8):3306-19.

4 Tabrizi SJ, Scahill RI, Durr A, et al. Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol 2011;10(1): 31-42.

5 Aylward E, Mills J, Liu D, et al. Association between Age and Striatal Volume Stratified by CAG Repeat Length in Prodromal Huntington Disease. PLoS Curr 2011; 3:RRN1235.

6 Rosas HD, Reuter M, Doros G, et al. A tale of two factors: what determines the rate of progression in Huntington’s disease? A longitudinal MRI study. Mov Disord 2011; 26(9):1691-7.

7 Gagnon KT, Pendergraff HM, Deleavey GF, et. al. Allele-selective inhibition of mutant huntingtin expression with antisense oligonucleotides targeting the expanded CAG repeat. Biochemistry 2010; 49(47):10166-78.

8 Fiszer A, Mykowska A, Krzyzosiak WJ. Inhibition of mutant huntingtin expression by RNA duplex targeting expanded CAG repeats. Nucleic Acids Res 2011; 39(13):5578-85.

9 Chung DW, Rudnicki DD, Yu L, Margolis RL. A natural antisense transcript at the Huntington’s disease repeat locus regulates HTT expression. Hum Mol Genet 2011; 20(17):3467 77.

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