Journal
NEUROBIOLOGY OF AGING
Volume 34, Issue 5, Pages 1504-1515Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2012.11.001
Keywords
Alpha-synuclein; Parkinson's disease; AMPK; Lactate
Categories
Funding
- National Institute of Health [P50-NS40256]
- Mayo Foundation
- Mangurian's Foundation
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Neuronal inclusions of alpha-synuclein (alpha-syn), termed Lewy bodies, are a hallmark of Parkinson disease (PD). Increased alpha-syn levels can occur in brains of aging human and neurotoxin-treated mice. Because previous studies have shown increased brain lactate levels in aging brains, in PD affected subjects when compared with age-matched controls, and in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP), we tested the effects of lactate exposure on alpha-syn in a cell-based study. We demonstrated that (1) lactate treatment led to alpha-syn accumulation and oligomerization in a time-and concentration-dependent manner; (2) such alterations were mediated via adenosine monophosphate-activated protein kinase (AMPK) and associated with increasing cytoplasmic phosphorylated AMPK levels; (3) AMPK activation facilitated alpha-syn accumulation and phosphorylation; (4) lactate treatment or overexpression of the active form of AMPK decreased alpha-syn turnover and neurite outgrowth; and (5) Lewy body-bearing neurons displayed abnormal cytoplasmic distribution of phosphorylated AMPK, which normally is located in nuclei. Together, our results suggest that chronic neuronal accumulation of alpha-syn induced by lactate-triggered AMPK activation in aging brains might be a novel mechanism underlying alpha-synucleinopathies in PD and related disorders. (C) 2013 Elsevier Inc. All rights reserved.
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