Heather D Durham, PhD
Heather Durham seeks to understand the mechanisms responsible for motor neuron diseases and peripheral neuropathies and to identify therapies to assist the vulnerable cells in defending themselves. Several genetic mutations responsible for familial forms of motor neuron diseases have been identified, which facilitates the establishment of cell culture and animal models to study in the laboratory. A common property of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), is an increased propensity of certain proteins to misfold, causing them to stick together, to associate with inappropriate partners, and to form insoluble aggregates in cells. These abnormalities occur in familial ALS because of genetic mutation, but also are generated through damage inflicted by the cellular environment in sporadic ALS.听
To study why misfolded proteins accumulate and upset the physiology of the cells most vulnerable to damage, Durham has created primary culture models by expressing mutant genes linked to inherited forms of the disease in motor neurons of mouse spinal cord cultures. Focus has been on ALS due to mutations in genes encoding SOD1 and RNA binding proteins (FUS, TDP-43). Using these cultures and transgenic mouse models, her research is linking the vulnerability of motor neurons to the way in which they respond to stress and deal with damaged proteins. The lab also has identified changes in chromatin remodeling in multiple forms of ALS including sporadic disease. In culture models, imaging methods are used to monitor biomarkers of disease progression and test the effectiveness of potential therapeutics. Findings in culture are then validated using complementary transgenic mouse models.听
The Durham lab works with the lab of Dr. Benoit Gentil to study the pathogenesis of ARSACS (Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay) and to develop a gene therapy approach to therapy.听听
Alecki C, Rizwan J, Le P, Jacob-Tomas S, Ming J, Xu S, Minotti S**, Wu T, Durham HD, Yeo GW, and Vera M.听 Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis, Nature Communications in press听
Pelaez MC, Fiore F, Larochelle N, Dabbaghizadeh A, Fern谩ndez Comaduran M, Arbour D, Minotti M, Marcadet L, Semann M, Robitaille R, Nalbantoglu JN, Sephton CF, and Durham HD.听 Reversal of cognitive deficits in FUSR521G amyotrophic lateral sclerosis mice by arimoclomol and a class I histone deacetylase inhibitor independent of heat shock protein induction. Neurotherapeutics 2024 Sep;21(5):e00388. doi: 10.1016/j.neurot.2024.e00388. Epub 2024 Jul 6. PMID:鈥�38972779听听
Fern谩ndez Comaduran M, Minotti S, Jacob-Tomas S, Rizwan J, Larochelle N, Robitaille R, Sephton CF, Vera M, Nalbantoglu JN, and Durham HD. Impact of histone deacetylase inhibition and arimoclomol on heat shock protein expression and disease biomarkers in primary culture models of familial ALS.听 Cell Stress and Chaperones 29:359-380. doi: 10.1016/j.cstres.2024.03.010听
Dabbaghizadeh A, Par茅 A, Cheng-Boivin Z, Dagher R, Minotti S, Dicaire MJ, Brais B, Young JC, Durham HD, Gentil BJ (2022) The鈥疛 domain of sacsin disrupts intermediate filament assembly. Int J Mol Sci. 23:15742. doi: 10.3390/ijms232415742.PMID:鈥�36555380听
Tibshirani M, Zhao B, Gentil BJ-C, Minotti S, Marques C, Keith J, Rogaeva E, Zinman L, Rouaux C, Robertson J, Durham HD (2017). Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis. Hum Mol Genet. 26:4142-4152. doi: 10.1093/hmg/ddx301听
Gentil BJ, C. Chalk, E. O鈥橣arrell, Santana LF, Durham HD, Massie R. (2017) A new mutation in FIG4 causes a severe form of CMT4J involving TRPV4 in the pathogenic cascade. J Neuropathol Exp Neurol 76:789-799. doi: 10.1093/jnen/nlx062听
Hooper, PL, Durham, HD, Torok, Z, Hooper, PL, Crul, T, and Vigh, L (2016). The central role of heat shock factor 1 in synaptic fidelity and memory consolidation. Cell Stress Chaperones 21:745-753 doi: 10.1007/s12192-016-0709-1听
Tibshirani M, Tradewell ML, Mattina KR, Minotti S, YangW, Zhou H, Strong MJ, Hayward LJ, Durham HD (2015). Cytoplasmic sequestration of FUS/TLS associated with ALS alters histone marks through loss of nuclear Protein Methyltransferase 1 Hum Mol Genet 24:773-86. doi: 10.1093/hmg/ddu494听
Lariviere R, Gaudet R , Gentil B, Girard M, Conte T , Minotti S, Leclerc-Desaulniers K, Gehring K , McKinney RA , Shoubridge EA , McPherson PS , Durham HD, Brais B (2015). Sacs knockout mice present pathophysiological defects underlying autosomal recessive spastic ataxia of Charlevoix-Saguenay. Hum Mol Genet 24:727-39. doi: 10.1093/hmg/ddu491听
Cha JRC, St. Louis K*, Gentil BJC, Tibshirani M. Tradewell ML, Minotti S, Jaffer ZM, Chen R, Rubenstein AE and Durham HD (2014). A novel small molecule HSP90 inhibitor, NXD30001, differentially induces heat shock proteins in nervous tissue in culture and in vivo Cell Stress Chaperones 19(3):421-35l. doi: 10.1007/s12192-013-0467-2听
Gentil BJC, Mushynski WE, Durham HD (2013) Heterogeneity in the properties of NEFL mutants causing Charcot-Marie-Tooth disease results in differential effects on neurofilament assembly and susceptibility to intervention by the chaperone-inducer, celastrol. Intl J Biochem Cell Biol 45:1499-508. doi: 10.1016/j.biocel.2013.04.009听
Kabashi E, Agar JN, Strong MJ, Durham HD (2012). Impaired proteasome function in sporadic amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis 13: 367鈥�371. doi: 10.3109/17482968.2012.686511听
