title: Adenosine monophosphate-activated protein kinase overactivation leads to accumulation of α-synuclein oligomers and decrease of neurites.
abstract: 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.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: Peizhou
authors.initials: P
authors.lastname: Jiang
authors.forename: Ming
authors.initials: M
authors.lastname: Gan
authors.forename: Abdul Shukkur
authors.initials: AS
authors.lastname: Ebrahim
authors.forename: Monica
authors.initials: M
authors.lastname: Castanedes-Casey
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Shu-Hui C
authors.initials: SH
authors.lastname: Yen
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D002478:Cells, Cultured; D019281:Dimerization; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D016501:Neurites / Q000378:metabolism* / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism*; D015854:Up-Regulation; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases