Robarts Research

Why I Became a Scientist

My interest has always been in understanding the nature of brain function and dysfunction, leading ultimately to a career in clinical neurology and neurobiological research.  In my clinical practice, my focus is on the diagnosis and treatment of individuals with amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease).  This focus has led to desire to further understand the inherent biology of motor neurons, and how this biology is disturbed in ALS.  Ultimately, by gaining this understanding we will be better positioned to develop novel treatment strategies for this devastating disorder.

 

Research Summary

My clinical research focuses on understanding the natural history of ALS, and in particular the occurrence of “non-motor” manifestations of the disease.  Most prominent amongst these are the findings of frontotemporal dysfunction, manifested as a behavioural syndrome, a dysexecutive syndrome, a cognitive syndrome or a florid frontotemporal dementia.  We have been specifically interested in the role of advanced neuroimaging techniques in determining who amongst the ALS population is at risk for one or more of these syndromes.  In the basic research realm, my research is focused on understanding the neuropathological substrate by which these syndromes occur, leading directly to our research on altered microtubule associated tau protein expression in ALS.  Our research into the biology of neurofilament metabolism in ALS has led directly to our discovery of alterations in mRNA metabolism in ALS and the characterization of unique mRNA binding proteins that regulate neurofilament mRNA stability.  We have characterized several of these proteins and demonstrated that the protein binding complex responsible for neurofilament mRNA stability is aberrant in ALS – a novel observation with significant biological and therapeutic implications.

Research Questions and Disease Implications

What are the characteristics of frontotemporal lobar dysfunction in ALS?

The presence of a frontotemporal syndrome in ALS is associated with a significant reduction in survivorship and is a critical point of dichotomization of ALS patients when considering therapeutic strategies. Moreover, the finding of such a syndrome fundamentally changes the concept of ALS from being a disorder restricted to the motor neurons, to one in which ALS is a multisystems disorder in which motor neurons are selectively but not exclusively vulnerable.

What is the nature of the neuropathology underlying the frontotemporal syndromes of ALS

We have characterized degenerating neocortical neurons in ALS with cognitive impairment as containing aberrant deposits of tau protein. We have shown that tau in ALS is aberrantly phosphorylated at threonine-175, that this phosphorylation is associated with increased insolubility of tau both ex vivo (extracted from ALS brain tissue) and in vitro (transfected cell lines with pseudo-phosphorylation thr-175 tau), and that this process is associated with an upregulation of GSK-3B expression in tau aggregate containing neurons. In vitro, the formation of tau aggregates can be inhibited with lithium – thus providing a critical therapeutic strategy for treating this specific aspect of ALS.

Is ALS an RNA mediated disorder?

We have observed that ALS-associated mutations in copper/zinc superoxide dismutase give rise to a novel mRNA binding protein that destabilizes NFL mRNA; that 14-3-3 proteins, known to form aggregates in ALS also regulate NFL mRNA stability; and that TDP-43, the most recently discovered ALS associated protein that is mutated in genetic variants of ALS, is also a NFL mRNA binding protein that stabilizes the mRNA transcript but fails to do so in ALS. We have discovered a novel mRNA binding protein (RGNEF) that is aberrantly expressed in ALS and are characterizing a panel of unique miRNAs that are aberrantly expressed in ALS. All of this data points strongly to a novel conceptualization of ALS as a RNA mediated disorder.

Education

• Protein Chemistry Methodology, University of Alabama at Birmingham, Dr. G.S.V. Johnson, 1992 (CIBA Foundation Bursar)
• Research Fellowship, Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, 1987-1990 (Supervisor: Ralph M. Garruto, PhD.; Laboratory Chief: D. Carleton Gajdusek, MD, Nobel Laureate)
• Recombinant DNA Methodology, Foundation for Advanced Education in the Sciences, Inc., National Institutes of Health, 1989
• Doctor of Medicine, 1978-82, Queen's University, Kingston, Ontario
• Undergraduate Biochemistry 1976-78, Queen's University

 

Training

• Resident, Neurology, 1984-87, University of Western Ontario
• Resident, Medicine, 1982-84, University of Western Ontario

Awards

• Queen Elizabeth II Diamond Jubilee Medal, 2012
• Fellow, Canadian Academy of Health Sciences, 2009
• Distinguished University Professor, University of Western Ontario, 2009
• Forbes Norris Award, International Alliance of ALS/MND Associations, 2008
• Fellow, The American Academy of Neurology, 2008
• Faculty Scholar Award, The University of Western Ontario, July 2006-2008
• Best Doctors in Canada Listing, 2002 – 2003; 2006-2007; 2007-2008
• Excellence in Teaching Award, University Student’s Council, University of Western Ontario, 2004, 2005, 2006, 2007, 2008
• Sheila Essay Award, American Academy of Neurology, April 2005
• Honorary Life Member, ALS Society of Canada
• Arthur J. Hudson Chair in ALS Research, 2001-current
• Hilda Glassman Award for Clinical Management Research, The ALS Association, 1999
• The Premier’s Research Excellence Award, 1999
• International Who’s Who of Professionals listing, 1996
• Medical Research Council of Canada Scholar, 1991-1996
• CIBA Foundation Symposium Bursary. Aluminum in Biology and Medicine, London, England, 1991
• Francis McNaughton Memorial Prize for Clinical Research, Canadian Congress of Neurological Sciences, Halifax, Nova Scotia, 1991
• Medical Research Council of Canada Fellowship, 1988-90• Health Research Personnel Development Program Fellowship, Ontario Ministry of Health, 1988-89 (declined)

Publications

• Yang W, Strong MJ.  Widespread neuronal and glial hyperphosphorylated tau deposition in ALS with cognitive impairment. Amyotroph Lateral Scler. 2012;13(2):178-193
• Volkening K, Strong MJ. RNA metabolism and neurodegenerative disease. RNA metabolism and neurodegenerative disease.  Curr Chem Biol 2011; (2):90-98
• Ince PG, Highley JR, Kirby J, Wharton SB, Takahashi H, Strong MJ, Shaw PJ. Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology.  Acta Neuropathol. 2011;122(6):657-671
• Strong MJ. The evidence for altered RNA metabolism in ALS. J Neurol Sci 2010; 288(1-2):1-12
• Volkening K, Leystra Lantz C, Yang WC, Jaffe H, Strong MJ. Tar DNA binding protein of 43 kDa (TDP-43), 14-3-3 proteins and copper/zinc superoxide dismutase (SOD1) interact to modulate NFL mRNA stability.  Implications for altered RNA processing in amyotrophic lateral sclerosis (ALS).  Brain Res. 2009;1305:168-82
• Strong MJ, Grace GM, Freedman M, Lomen-Hoerth C, Woolley S, Goldstein LH, Murphy J, Shoesmith C, Rosenfeld J, Leigh PN, Bruijn L, Ince P, Figlewicz D. Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis.  Amyotrophic Lateral Sclerosis 2009;10(3):131-46
• Moisse K, Mepham J, Volkening K, Welch I, Hill T, Strong MJ.  Cytosolic TDP-43 expression following axotomy is associated with caspase 3 activation in NFL-/- mice: support for a role for TDP-43 in the physiological response to neuronal injury.  Brain Research 2009;1296:176-86
• Gohar M, Yang W, Strong W, Volkening K, Leystra-Lantz C, Strong MJ.  Tau phosphorylation at ¹⁷⁵Thr leads to fibril formation. Implications for the tauopathy of amyotrophic lateral sclerosis. J Neurochem 2009 Feb;108(3):634-43. Epub 2008 Nov 19
• Moisse K, Volkening K, Leystra-Lantz C, Welch I, Hill T, Strong MJ. Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy.  Brain Research 2009 Jan 16;1249:202-11
• Strong MJ.  The syndromes of frontotemporal dysfunction in amyotrophic lateral sclerosis.  Amyotrophic Lateral Sclerosis 2008;9(6):323-338
• Yang W, Leystra-Lantz C, Strong MJ.  Upregulation of GSK3beta expression in frontal and temporal cortex of ALS with cognitive impairment (ALSci). Brain Research 2008;1196:131-139
• Strong MJ, Volkening K, Hammond R, Wang WC, Strong W, Leystra-Lantz C, Shoesmith C.  TDP43 is a human low molecular weight neurofilament (hNFL) mRNA binding protein.  Mol Cell Neurosci. 2007;35(2):320-327

Contact Information

Denise Deschenes (Dean's office):
Phone: 519-661-2111 x81190 Fax: 519-850-2357
Email: Denise.Deschenes@schulich.uwo.ca

Betsy Toth (clinical administrative secretary):
Phone: 519-663-3874 Fax: 519-663-3609
Email: Betsy.Toth@lhsc.on.ca