Adenosine monophosphate-activated protein kinase overactivation leads to accumulation of α-synuclein oligomers and decrease of neurites

• Published in: Neurobiology of aging Vol. 34; no. 5; pp. 1504 - 1515
• Main Authors: Jiang, Peizhou, Gan, Ming, Ebrahim, Abdul Shukkur, Castanedes-Casey, Monica, Dickson, Dennis W., Yen, Shu-Hui C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2013
• Subjects: Alpha-synuclein; alpha-Synuclein - chemistry; alpha-Synuclein - metabolism; AMPK; Animals; Cells, Cultured; Dimerization; Enzyme Activation; Humans; Internal Medicine; Lactate; Mice; Neurites - metabolism; Neurites - pathology; Neurology; Parkinson's disease; Protein Kinases - metabolism; Up-Regulation; AMPK; Parkinson's disease; Lactate; Alpha-synuclein
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2012.11.001

Neuronal inclusions of α-synuclein (α-syn), termed Lewy bodies, are a hallmark of Parkinson disease (PD). Increased α-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 α-syn in a cell-based study. We demonstrated that (1) lactate treatment led to α-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 α-syn accumulation and phosphorylation; (4) lactate treatment or overexpression of the active form of AMPK decreased α-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 α-syn induced by lactate-triggered AMPK activation in aging brains might be a novel mechanism underlying α-synucleinopathies in PD and related disorders.