کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
6806163 1433570 2014 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Pathogenic effects of amyotrophic lateral sclerosis-linked mutation in D-amino acid oxidase are mediated by D-serine
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی سالمندی
پیش نمایش صفحه اول مقاله
Pathogenic effects of amyotrophic lateral sclerosis-linked mutation in D-amino acid oxidase are mediated by D-serine
چکیده انگلیسی
Amyotrophic lateral sclerosis is a neuromuscular disease characterized by selective loss of motor neurons leading to fatal paralysis. We previously reported a coding mutation in D-amino acid oxidase (R199W DAO) associated with familial amyotrophic lateral sclerosis. DAO metabolizes D-serine, a co-agonist at the N-methyl-D-aspartic acid receptor. We investigated the mechanisms mediating the pathogenic effects of R199W DAO on motor neuron survival and showed that expression of glial R199W DAO is sufficient to induce apoptosis in cocultured motor neurons and this is sensitive to 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, an N-methyl-d-aspartic acid receptor antagonist selective for the D-serine/glycine site. R199W DAO activates protein aggregation and autophagy, which is also sensitive to this antagonist. Using immunocytochemistry, we showed that D-serine and DAO were abundant in spinal cord motor neurons and depleted in amyotrophic lateral sclerosis. In summary, the toxic effects of R199W DAO on motor neurons can be mediated directly by expression in motor neurons or by astrocytes in coculture, R199W DAO promotes autophagy and its pathogenic effects are at least in part mediated via the N-methyl-d-aspartic acid receptor.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neurobiology of Aging - Volume 35, Issue 4, April 2014, Pages 876-885
نویسندگان
, , , , ,