Stabilization of alpha-synuclein protein with aging and familial parkinson's disease-linked A53T mutation.
We examined the potential relationship between aging and alpha-synuclein (alpha-Syn) metabolism, both of which are implicated in the pathogenesis of Parkinson's disease (PD) and other alpha-synucleinopathies. During aging,alpha-Syn and beta-Syn mRNA expression in brain decreases, but the protein levels are maintained at high levels. Significantly, the alpha-Syn protein level increases with aging in human substantia nigra. Pulse-chase analyses of alpha-Syn half-lives in neurons and neuronal cell lines indicate that, in mature neurons, the expression of alpha-Syn is regulated by the post-translational stabilization of alpha-Syn protein. Moreover, A53T mutant human alpha-Syn exhibits increased stability in neuronal cell lines, leading to higher levels of the mutant protein in cells and transgenic mice. Inhibitor studies suggest that the proteasomal and lysosomal systems may not be responsible for the differential stabilization or metabolism of alpha-Syn protein in neuronal cells. Because increased stabilization of alpha-Syn protein is associated with increased protein levels and accumulation of pathogenic protein modifications, such as oxidative damage, the stabilization of alpha-Syn with aging may be a significant factor in the pathogenesis of alpha-synucleinopathies.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA.
Wenxue
W
Li
Christian
C
Lesuisse
Yanqun
Y
Xu
Juan C
JC
Troncoso
Donald L
DL
Price
Michael K
MK
Lee
D000375:Aging; D000818:Animals; D001921:Brain / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D008247:Lysosomes / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000235:genetics*; D017354:Point Mutation; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein
D015853:Cysteine Proteinase Inhibitors; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex