Ascorbate availability and neurodegeneration in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease in which upper and lower motoneurons progressively deteriorate and die. Neuronal damage is most evident in the lower central nervous system, and death generally occurs following central respiratory failure. Proposed and demonstrated mechanisms for amyotrophic lateral sclerosis are diverse, and include altered superoxide dismutase and neurofilament proteins, autoimmune attack, and hyperglutamatergic activity. However, they do not account for the late onset of the disease, its earlier onset in males, and the differential vulnerability of neurons located in the brainstem and spinal cord. It is proposed here that, within the context of a specific defect such as altered superoxide dismutase, age-dependent decline in ascorbate availability triggers the disease. A role for ascorbate, which is found in millimolar levels in neurons, is suggested by a number of consistencies: 1) superoxide radicals being a common substrate for superoxide dismutase and ascorbate; 2) a close association between central nervous system ascorbate levels and injury tolerance; 3) a steady decline in ascorbate plasma levels and cellular availability with age; 4) plasma ascorbate levels being lower in males; 5) an association of ascorbate release with motor activity in central nervous system regions, in vivo; 6) the coupling of brain-cell ascorbate release with glutamate uptake; 7) possible roles for ascorbate modulation of N-methyl-D-aspartate receptor activity; 9) the ability of ascorbate to prevent peroxynitrite anion formation; and 10) evidence supporting the scorbutic guinea pig as a model for amyotrophic lateral sclerosis. Emphasis is placed on the probable competition between superoxide dismutase and ascorbate within the context of a primary defect of metal-binding or metal access in high-concentration proteins such as superoxide dismutase and human heavy neurofilaments. Finally, distinct features of alpha-motoneuronal physiology suggest that cell physiological characteristics such as high metabolic activity and extensive calcium dynamics may render neurons differentially vulnerable in amyotrophic lateral sclerosis.