title: Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis.
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.
authors.affiliation: Geriatric Research, Education and Clinical Center, Veterans Administration Hospital, Madison, WI 53705, USA.
authors.forename: Sivan
authors.initials: S
authors.lastname: Vadakkadath Meethal
authors.forename: Craig S
authors.initials: CS
authors.lastname: Atwood
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology
chemical_list: D019344:Lactic Acid