Heather D Durham, PhD
Heather Durham seeks to understand the mechanisms responsible for motor neuron diseases 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.
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 SOD1 and in 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. Recently, the lab has identified changes in chromatin remodeling in multiple forms of ALS including sporadic disease. They are testing two approaches for intervention: Histone deacetylase inhibitors to restore chromatin function and inducers of heat shock proteins that act as molecular chaperones to handle misfolded proteins. The combination of these drugs also is being tested to determine if they act synergistically. In culture models, advanced imaging methods are used to monitor biomarkers of disease progression. Findings in culture are then validated using complementary transgenic mouse models.
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
Gentil BJ, C. Chalk, E. O’Farrell, 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
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
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
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
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
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
Kabashi E, Agar JN, Strong MJ, Durham HD (2012). Impaired proteasome function in sporadic amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis 13: 367–371. doi: 10.3109/17482968.2012.686511