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.