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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS044154-02
Application #
6805528
Study Section
Nutrition Study Section (NTN)
Program Officer
Refolo, Lorenzo
Project Start
2003-09-30
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$154,500
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Hensley, Kenneth (2015) Detection of Protein Carbonyls by Means of Biotin Hydrazide-Streptavidin Affinity Methods. Methods Mol Biol 1314:95-100
Hensley, Kenneth; Christov, Alexandar; Kamat, Shekhar et al. (2010) Proteomic identification of binding partners for the brain metabolite lanthionine ketimine (LK) and documentation of LK effects on microglia and motoneuron cell cultures. J Neurosci 30:2979-88
Hensley, Kenneth (2010) Neuroinflammation in Alzheimer's disease: mechanisms, pathologic consequences, and potential for therapeutic manipulation. J Alzheimers Dis 21:1-14
Neymotin, Arie; Petri, Susanne; Calingasan, Noel Y et al. (2009) Lenalidomide (Revlimid) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis. Exp Neurol 220:191-7
Zhang, Wenchi; Wang, Liang; Liu, Yijin et al. (2009) Structure of human lanthionine synthetase C-like protein 1 and its interaction with Eps8 and glutathione. Genes Dev 23:1387-92
Hensley, Kenneth (2009) Detection of protein carbonyls by means of biotin hydrazide-streptavidin affinity methods. Methods Mol Biol 536:457-62
Kamat, Chandrashekhar D; Gadal, Sunyana; Mhatre, Molina et al. (2008) Antioxidants in central nervous system diseases: preclinical promise and translational challenges. J Alzheimers Dis 15:473-93
Chung, Charlotte H Y; Kurien, Biji T; Mehta, Padmaja et al. (2007) Identification of lanthionine synthase C-like protein-1 as a prominent glutathione binding protein expressed in the mammalian central nervous system. Biochemistry 46:3262-9
Hensley, Kenneth; Mhatre, Molina; Mou, Shenyun et al. (2006) On the relation of oxidative stress to neuroinflammation: lessons learned from the G93A-SOD1 mouse model of amyotrophic lateral sclerosis. Antioxid Redox Signal 8:2075-87
Mhatre, Molina; Hensley, Kenneth; Nguyen, Albert et al. (2006) Chronic thrombin exposure results in an increase in apolipoprotein-E levels. J Neurosci Res 84:444-9

Showing the most recent 10 out of 17 publications