Strong

M.J. Strong

Professor
Chair, Clinical Neurological Sciences

M. D. Queen's University


Office: LHSC-UH & RRI 3-15C.1
Phone: (519) 663-3874
Fax: (519)
E-mail: mstrong@uwo.ca

Clinical Activities

Keywords:

Research Interests

Keywords: Motor Neuron Disease, Neurofilament Metabolism, Aluminum Neurotoxicity

Description of Research Activities

Our research has focused on developing an understanding of the pathogenesis of amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease). We have been specifically interested in the mechanisms by which intraneuronal neurofilamentous aggregates are induced to form in the disease, and the process by which such aggregates might lead to cell death. To this end, we have two broad experimental approaches: the first, utilizing paradigms of acute and chronic aluminum neurotoxicity to model the clinicopathological characteristics of the disease; and, secondly, the neurochemical study of postmortem tissue from patients with ALS.

In the former, we have shown that the intracisternal inoculation of aluminum chloride in young adult New Zealand white rabbits induces neurofilamentous aggregates by inducing post translational modifications in the high molecular weight neurofilament subunit protein (NFH) that increases its binding avidity for microtubules. In a model of chronic aluminum neurotoxicity in which many of the clinical and ultrastructural characteristics of ALS are recapitulated, we have shown that motor neurons can recover, and that this recovery potential is dependant on the extent of microglial proliferation in response to the neuronal injury. This has led to our current working hypothesis in which the propagation of ALS is independent of the initial disease trigger, but dependant on the non-neuronal response to it.

Our studies of ALS initially focused on the role of excessive reactive nitrating species generation, and in doing so, defined a novel function of the low molecular weight neurofilament (NFL) protein as a biological "sink" for free nitronium species. Although we demonstrated no significant difference in the extent of NFL nitration when ALS was compared to control tissue, ALS motor neurons may have a deficit in their ability to protect from toxicity by nitrating species by virtue of a deficiency in steady state NFL mRNA. In current studies, we are pursuing the role of NFL in protecting against such damage, and also the role of increased neuronal nitric oxide synthase (nNOS) activity in susceptible populations of spinal motor neurons. The role of microglia cells in providing the final determinant of neuronal death is also being studied.

 

Selected Publications

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