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Arthur Horwich, MD

Sterling Professor of Genetics and Professor of Pediatrics

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Arthur Horwich, MD

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Research Summary

We are focused on misfolding-induced neurodegeneration caused by mutant forms of the cytosolic enzyme superoxide dismutase (SOD1), which produce a dominant-inherited form of ALS (Lou Gehrig’s Disease) with progressive motor neuron dysfunction that leads to lethal paralysis. Mutant SOD1-linked ALS accounts for ~2% of all ALS cases and ~20% of genetically-associated ALS. Notably, inherited and non-inherited forms of ALS in humans are indistinguishable at a clinical level. We are using mice overexpressing a mutant G85R SOD1-YFP fusion protein to study the mechanism of disease causation. The mouse model studied affords one of the most powerful approaches to following the development of this so far non-treatable neurodegenerative condition. The hope is that basic understanding may lead to directed therapy.

Extensive Research Description

Studies of the past decades have shown that many diseases of neurodegeneration are associated with protein misfolding and aggregation of specific proteins in particular neurons or glia, and we have been studying one such mechanism of degeneration. We have focused on misfolding/aggregation caused by mutant forms of the anti-oxidant cytosolic enzyme SOD1 (superoxide dismutase), which produces dominant-inherited ALS, with progressive paralyzing motor neuron dysfunction. We are using mice overexpressing mutant G85R SOD1-YFP, containing a mutant version of SOD1 unable to reach the native state, studying the transgenic animals with a variety of approaches to investigate how the mutant SOD1 produces motor dysfunction.

We have identified that there is a progression of misbehavior of mutant SOD1 protein itself in the spinal cord motor neurons of transgenic animals. Initially it is soluble and associated to a significant extent with the abundant cytosolic chaperone Hsc70 (by contrast to the wild-type protein, which does not form such association, presumably because it occupies the native homodimeric state). Subsequently, the mutant SOD1 proteiin begins to form both soluble oligomers (observable by gel filtration chromatography) and insoluble aggregates, and at this point an additional molecular chaperone, Hsp110, becomes associated with the soluble aggregates. A portion of the aggregates becomes insoluble and forms large structures in the cytosol of motor neurons. These cells become surrounded by microglia and appear to be subsequently removed. Associated with such loss, the affected animal initially exhibits mild lower extremity symptoms (weakness or pulling in when held by the tail at ~ 3 months of age), which progresses over the next 3-4 months to paralysis, usually commencing in the lower extremities.

We have used laser capture microdissection of motor neurons and RNA-seq from animals at mid-course to inspect for changes in transcriptional expression, but find only a small number of differences relative to the motor neurons from wild-type SOD1-YFP mice. Notably, there is no classical heat shock response beyond induction of Hsp110 and no ER unfolded protein response, but there are effects on several calcium binding proteins. We surmised that most of the toxicity of mutant SOD1 is exerted post-translationally. In collaboration with David McCormick’s group we carred out electrophysiologic measurements of motor neurons by patch clamping them in spinal cord of wild-type and mutant SOD1 mice in novel rapidly prepared slice preparations. This identified that the fast-firing motor neurons, which innervate fast twitch muscle, are the first to be lost. This observation was confirmed by studying wild-type or mutant mice running on a wheel while simultaneously monitoring single motor neurons in the ventral horn of the spinal cord by field potential measurements and the firing of corresponding lower extremity muscles. Most recently we have been screening a number of candidate genes for prolongation of the survival of the mutant ALS mice.

Research Interests

Amyotrophic Lateral Sclerosis; Genetics; Motor Neurons; Neurosciences; Pediatrics; Superoxide Dismutase; Protein Folding; Neurodegenerative Diseases

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