By: Lise Munsie, PhD
Investigators across Canada are heavily involved in HD research; these teams tackle a broad array of HD related research topics ranging from basic cell biology and biochemistry of the huntingtin (Htt) protein, to therapeutic leads and large clinical trials.
On the east coast, Dr. Eileen Denovan-Wright’s lab at the University of Dalhousie focuses on the cell biology of Htt in mouse models. Her group explores altered gene expression and its consequences in the brain. Their current research focuses on cannabanoid receptors. Dr. Denovan-Wright’s group recently published a manuscript that looks at the dysregulation of genes in the cytokine and endocannabinoid systems in HD. They posit that activation of p65/ RelA, which co-regulates expression of cytokine and endocannabinoid receptor genes, may prove beneficial in HD.1
In Ontario, Dr. Ray Truant’s lab at McMaster University is looking at the normal function of Htt and related dysfunction of mHtt, using cell models and biophotonic techniques.Dr. Truant’s lab uses advanced and elegant techniques, described in their recent paper published in Human Molecular Genetics, that looks at fluorescently tagged Htt, in aggregates, in live cells.2 Also in Ontario, Dr. Mark Guttman, a movement disorder neurologist affiliated with the University of Toronto, is heavily involved in PREDICT-HD, as well as caring for HD patients across the province.
In the prairies, Dr. Simonetta Sipione’s lab at the University of Alberta uses a multi-disciplinary approach to study mechanisms behind HD for the drug discovery pipeline. In the past year this group uncovered GM1 as a therapeutic lead for HD treatment.3
Finally, the west coast province of British Columbia is a hotbed for HD research.
The Centre for Molecular Medicine and Therapeutics, affiliated with the University of British Columbia (UBC), houses the labs of Dr. Michael Hayden (see HD Insights, vol. 4) and Dr. Blair Leavitt (see HD Insights, vol. 3). These multi-faceted labs perform advanced HD research, including elucidating molecular mechanisms involved in the progression of HD, using many different mouse models.4 Dr. Hayden’s group has been heavily involved in developing therapeutics for HD, specifically antisense oligonucleotide (ASO) development for in vivo Htt knockdown (see HD Insights, vol. 3).5 In addition to their laboratory work, both Dr. Leavitt and Dr. Hayden are heavily involved in clinical trials, including the TRACKHD study,6 patient-based research, and HD genetic research.7 Also at UBC, Dr. Lynn Raymond’s lab specializes in neuroscience-related techniques including electrophysiology.8 With respect to HD, her group investigates the role of neurotransmitter receptors and the neuron-specific role of Htt and related dysfunction in HD.9
1 Laprairie RB, Warford JR, Hutchings S, et al. The cytokine and endocannabinoid systems are co-regulated by NF-kappaB p65 RelA in cell culture and transgenic mouse models of Huntington’s disease and in striatal tissue from Huntington’s disease patients. J Neuroimmunol. 2013 Dec 12; pii: S0165-5728(13)00339-1. doi: 10.1016/j.jneuroim.2013.12.008.
2 Caron NS, Hung CL, Atwal RS, Truant R. Live cell FRET and protein dynamics reveal two types of mutant huntingtin inclusions. Hum Mol Genet. 2013 Dec 11; doi: 10.1093/hmg/ddt625.
3 Di Pardo A, Maglione V, Alpaugh M, et al. Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice. Proc Natl Acad Sci USA. 2012 Feb 28; 109(9):3528-33. doi: 10.1073/pnas. 1114502109.
4 Mazarei G, Budac DP, Lu G, et al. Age-dependent alterations of the kynurenine pathway in the YAC128 mouse model of Huntington disease. J Neurochem. 2013 Dec; 127(6):852-67. doi:10.1111/jnc.12350.
5 Ostergaard ME, Southwell AL, Kordasiewicz H, et al. Rational design of antisense oligonucleotides targeting single nucleotide polymorphisms for potent and allele selective suppression of mutant Huntingtin in the CNS. Nucleic Acids Res. 2013 Nov; 41(21):9634-50.
6 Franciosi S, Shim Y, Lau M, Hayden MR, Leavitt BR. A systematic review and meta-analysis of clinical variables used in Huntington disease research. Mov Disord. 2013 Dec;28(14): 987-94. doi: 10.1002/mds.25663.
7 Semaka A, Hayden M. Evidence-based genetic counselling implications for Huntington disease intermediate allele predictive test results. Clin Genet. 2013 Nov 20; doi: 10.1111/ cge.12324.
8 Milnerwood AJ, Parsons MP, Young FB, et al. Memory and synaptic deficits in Hip14/DHHC17 knockout mice. Proc Natl Acad Sci USA. 2013 Nov 25; 110:20296-20301.
9 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.
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