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Grant Abstract: No Damage to Folate Cycle in the Central Nervous System

Grant Number: 1R01NS044154-01A1
PI Name: Kenneth Hensley
Project Title: No Damage to Folate Cycle in the Central Nervous System

Abstract: DESCRIPTION (provided by applicant): Epidemiological data indicates that components of the folic acid pathway of one-carbon metabolism are compromised in aged humans, and more so in cases of dementia (such as Alzheimer's disease, AD) or motor neuron disease (such as amyotrophic lateral sclerosis, ALS). Moreover, rare congenital defects in folate pathway enzymes inevitably precipitate neurological disease. No explanations have been found to explain why the folate cycle is impaired in the aged individuals or those with neurological disease. Our laboratory has documented a pattern of protein oxidation in AD brain and in an animal model for ALS that suggests a mechanism for folate cycle impairment. We hypothesize that reactive nitrogen species (RNS) generated endogenously within the aging CNS damage key enzymes of the folate pathway, particularly the vitamin B12-dependent methionine synthase (MS), contributing to neurological disease. The corollary to this hypothesis is that nutritional supplementation strategies aimed at bolstering function of the folate cycle, particularly at the level of the MS enzyme, should mitigate some types of CNS degenerating. We seek to begin critically testing these ideas in five specific aims whose goals are as follows: (1) Determine folate cycle enzyme levels and activities in regions of the AD brain known to differentially experience RNS stress. (2) Determine whether folate cycle enzyme levels and activities are reduced in an accepted animal model for familial ALS (namely the G93A-SOD1 transgenic mouse, which experiences motor neuron degeneration commensurate with protein oxidation and nitration) and whether disease in this animal is mitigated by nutritional supplementation with folic acid plus vitamin B12 (cobalamin) analogs. (3) Determine whether folic acid, alone or in combination with cobalamin analogs, protects the folate cycle integrity in astrocytes or neurons challenged directly with nitric oxide (NO). (4) Determine whether NO inactivates MS solely by formation of a nitrosyl-cobalamin complex or through generation of secondary carbon-centered and oxyradicals and whether this process directly precipitates loss of function in the MS holoenzyme.

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