Research Round-Up

By: Lise Munsie, PhD

In pharma…

The well-tolerated, FDA-approved drug metformin is an antidiabetic drug that mimics caloric restriction. Jin and colleagues tested their hypothesis that it may also counteract pathways affected by the presence of mHTT using the striatal Q111 cell model.1 Under serum starvation conditions, the drug corrected phenotypes such as decreased ATP production, increased LDH release, and decreased mitochondrial membrane potential, and modulated the balance between mitochondrial fusion and fission genes by activating the AMPK pathway. The group confirmed that metformin crossed the blood-brain barrier, and that increased levels of p-AMPK could be found in the brain post-administration, suggesting that this drug could be used as a neuroprotectant in HD.

The drug topotecan, a topoisomerase 1 inhibitor, leads to the activation of Ube3a, a ubiquitin ligase implicated in mHTT clearance. In a recent article in Human Molecular Genetics, Shekhar and colleagues report on their study in which topetecan delivery was optimized and tested for symptomatic improvement in the R6/2 HD mouse model.2 The drug partially rescued striatal atrophy and decreased mHTT aggregate load. The group saw upregulation of Ube3a in the brain, and a decrease in wildtype and mutant htt levels. Although side effects on other affected genes must be carefully monitored, this drug may move forward as one that delays HD progression.

The Tingle group investigated the hypothesis that dysfunctional cholinergic neurotransmission through a loss of agonist contributes significantly to HD pathology.3 The group attempted pharmacological replacement using the nicotine analogue and partial agonist varenicline. Chronic exogenous administration to YAC128 HD model mice resulted in motor and behavioral improvements combined with improved neuorophysiological phenotypes. Varenicline is approved for other disorders, and its multi-targeted and direct effects makes it a promising candidate for further study.


1Jin J, Gu H, Anders NM, et al. Metformin protects cells from mutant huntingtin toxicity through activation of AMPK and modulation of mitochondrial dynamics. Neuromolecular Med. 2016 Dec;18(4):581-592.

2Shekhar S, Vatsa N, Kumar V, et al. Topoisomerase 1 inhibitor topotecan delays the disease progression in a mouse model of Huntington’s disease. Hum Mol Genet. 2016 Dec 22.

3McGregor AL, D’Souza G, Kim D, Tingle MD. Varenicline improves motor and cognitive deficits and decreases depressive-like behaviour in late-stage YAC128 mice. Neuropharmacology. 2016 Dec 23;116:233-246.

In patient studies…

Detailed genetic analysis of HD is important for improving targeted therapies. The Hayden lab reports on HD haplotypes in the Latin American population.1 By genotyping Peruvian HD patients, the group identifies the HD mutation on the A1 HTT haplotype, a haplotype also common in European HD patients. The group defines an Amerindian-specific A1 variant based on single nucleotide polymorphism (SNP) analysis in this population. This is the most frequent HD haplotype in the studied population. This finding shows a distinct genetic origin between HD patients on Amerindian and European origin in Latin America, but still a common genetic target.

Studying genes that affect the age of onset of disease can uncover pathways involved in HD progression. In a recent article, a Spanish group probes the association between SNPs in the melanocortin 1 receptor gene (MCR1) and age of onset in the Spanish HD population.2 MCR1 is involved in anti-oxidant and cell stress pathways. Variants in this allele occur at a normal frequency in the HD population. Using a multiple linear regression model, the group show that the p.R151C polymorphism, a mutation that affects the protein’s function, may decrease the age of onset of clinical signs in Spanish HD patients, which suggests this protein and pathway may be worthy of further study.

The Milek group examined cardiovascular pathology of HD in patients.3 Expression of mHTT has negative consequences in non-neuronal tissues, and heart disease may factor into deaths in HD patients. This led the group to compare individuals with HD at different stages of disease progression, and age-matched controls. Although not significant between all groups, there was an overall increased risk for coronary heart disease in HD patients. Specific measures showed arterial dysfunction including significantly decreased distensibility of the carotid arterial wall in presymptomatic HD patients. Further and larger studies will be required to elucidate full vascular pathology in HD patients.


1Kay C, Tirado-Hurtado I, Cornejo-Olivas M, et al. The targetable A1 Huntington disease haplotype has distinct Amerindian and European origins in Latin America. Eur J Hum Genet. 2016 Dec 21.

2Tell-Marti G, Puig-Butille JA, Gimenez-Xavier P, et al. The p. R151C polymorphism in MC1R gene modifies the age of onset in Spanish Huntington’s Disease patients. Mol Neurobiol. 2016 Dec 6:1-5.

3Kobal J, Cankar K, Pretnar J, et al. Functional impairment of precerebral arteries in Huntington disease. J Neurol Sci. 2017 Jan 15;372:363-368.

In pathways…

An exciting study from the Truant lab examines endogenous HTT function in live human cells.1 They identify HTT at sites of DNA damage, localized to DNA repair proteins during induced oxidative stress. This localization is dependent on the activity of ataxia telangiectasia mutated (ATM) protein, a kinase that has been shown to contribute to HD progression in mouse models. The group hypothesize that inhibiting ATM activity, which slows or inhibits mHTT recruitment to sites of DNA damage, may have therapeutically beneficial effects in HD.

Transcriptional dysregulation is a hallmark of HD. The Jones group focuses their pathway study on differential gene expression upon epidermal growth factor (EGF) stimulation in two cellular models of HD.2 The group found that regulatory genes within the TGFβ signaling pathway were differentially expressed in cells harboring the expanded allele, and many were associated with SMAD transcription factors (TFs). The group shows that stimulation with TGFβ1 activates SMAD TFs, leading to nuclear localization. This nuclear translocation is altered in cells that express mHTT. They additionally demonstrate direct binding of SMAD3 to HTT in the cells, showing that these proteins may directly affect HTT expression. The group concludes that TGFβ signaling is a possible target for disease modification and could prove to be a useful biomarker for disease progression.

HD patients have decreased levels of striatal phosphodiesterase 10 (PDE10), an enzyme that hydrolyzes cyclic AMP and GMP. Acute inhibition of PDE10 can partially restore the basal ganglia circuitry in HD models. A manuscript in Neuron3 extensively examines the neurophysiology associated with acute PDE10 inhibition in two mouse models that recapitulate the pre-existing PDE10 deficit. Using electrophysiological and proteomic approaches, the group defines how corticostriatal transmission is altered and subsequently improved in these models under PDE10 inhibition, specifically probing the striatal indirect pathway.


1Maiuri T, Mocle AJ, Hung CL, et al. Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex. Hum Mol Genet. 2016 Dec 25.

2Bowles KR, Stone T, Holmans P, Allen ND, Dunnett SB, Jones L. SMAD transcription factors are altered in cell models of HD and regulate HTT expression. Cell Signal. 2016 Dec 14;31:1-14.

3Beaumont V, Zhong S, Lin H, et al. Phosphodiesterase 10A inhibition improves cortico-basal ganglia function in Huntington’s disease models. Neuron. 2016 Dec 21;92(6):1220-1237.