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…
The 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.