cobamamide and Disease-Models--Animal

Missense mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) cause the majority of familial and some sporadic forms of Parkinson's disease (PD). The hyperactivity of LRRK2 kinase induced by the pathogenic mutations underlies neurotoxicity, promoting the development of LRRK2 kinase inhibitors as therapeutics. Many potent and specific small-molecule LRRK2 inhibitors have been reported with promise. However, nearly all inhibitors are ATP competitive-some with unwanted side effects and unclear clinical outcome-alternative types of LRRK2 inhibitors are lacking. Herein we identify 5'-deoxyadenosylcobalamin (AdoCbl), a physiological form of the essential micronutrient vitamin B

Topics: Allosteric Regulation; Animals; Caenorhabditis elegans; Cobamides; Disease Models, Animal; Drosophila melanogaster; Drug Repositioning; HEK293 Cells; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Parkinson Disease; Rats; Vitamin B 12; Vitamin B Complex

The pathogenesis of multiple sclerosis (MS) begins with an infection by a bacterium from the class of bacteria that produce and utilize adenosylcobalamin (AdoCbl) and possess an adenosyl transferase enzyme (ATR); these bacteria are the exogenous antigens that cause MS. Human ATR is homologous to bacterial ATR and B cells produce anti-ATR antibodies as an autoimmune response thereby reducing the concentration of ATR and thus limiting production of AdoCbl, one of the two bioactive forms of vitamin B12. The next step in MS pathogenesis is a period of subclinical AdoCbl deficiency over a period of many years resulting in production of odd-carbon-number fatty acids that are incorporated into myelin rendering it antigenic. The next step in MS pathogenesis is breach of the blood brain barrier thereby introducing leukocytes into the brain's blood supply resulting in T cell attack of antigenic myelin. All epidemiological clusters are regions wherein the major agricultural products are legumes that produce a high percentage of odd-carbon-number fatty acids and contain symbiotic rhizobia type bacteria in root nodules and in the soil. This novel etiological hypothesis is called "multiple sclerosis due to adenosylcobalamin deficiency" (MS-AdoCbl). Creation of realistic animal models based on the MS-AdoCbl hypothesis is presented. Methods for testing predictions made by the MS-AdoCbl hypothesis are described.

Topics: Adenosine Triphosphate; Animals; Autoimmunity; B-Lymphocytes; Blood-Brain Barrier; Cobamides; Disease Models, Animal; Fatty Acids; Humans; Male; Methionine Adenosyltransferase; Mice; Models, Biological; Multiple Sclerosis; Rhizobium; T-Lymphocytes; Vitamin B 12