Document Type

Journal Article

Publisher

Elsevier

Faculty

Faculty of Computing, Health and Science

School

School of Exercise, Biomedical and Health Science / Centre of Excellence for Alzheimer's Disease Research and Care

RAS ID

10698

Comments

This is an Author's Accepted Manuscript of: Vadakkadath Meethal, S., & Atwood, C.S. (2010). Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis. NOTICE: this is the author’s version of a work that was accepted for publication in Neurobiology of Aging. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A version was subsequently published in Neurobiology of Aging. Available here.

Abstract

Amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease) is a progressive debilitating neurodegenerative disease with no cure. We propose a novel molecular model for the pathogenesis of ALS that involves an adenosine triphosphate (ATP)-dependent muscle neuronal lactate shuttle (MNLS) at the neuromuscular junction (NMJ) to regulate the flow of lactate from muscle to neurons and vice versa. Failure of the MNLS due to respiratory chain dysfunction is proposed to result in lactate toxicity and degeneration of nerve endings at the NMJ leading to nerve terminus dysjunction from the muscle cell. At a critical threshold where denervation outpaces reinnervation, a vicious cycle is established where the remaining innervated muscle fibers are required to work harder to compensate for normal function, and in so doing produce toxic lactate concentrations which induces further denervation and neuronal death. This mechanism explains the exponential progression of ALS leading to paralysis. The molecular events leading to the dysregulation of the MNLS and the dismantling of NMJ are explained in the context of known ALS familial mutations and age-related endocrine dyscrasia. Combination drug therapies that inhibit lactate accumulation at the NMJ, enhance respiratory chain function, and/or promote reinnervation are predicted to be effective therapeutic strategies for ALS.

DOI

10.1016/j.neurobiolaging.2010.04.012

Access Rights

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Link to publisher version (DOI)

10.1016/j.neurobiolaging.2010.04.012