Stabilization of α-synuclein protein with aging and familial Parkinson's disease-linked A53T mutation

Wenxue Li, Christian Lesuisse, Yanqun Xu, Juan C Troncoso, Donald L. Price, Michael K. Lee

Research output: Contribution to journalArticle

Abstract

We examined the potential relationship between aging and α-synuclein (α-Syn) metabolism, both of which are implicated in the pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies. During aging, α-Syn and β-Syn mRNA expression in brain decreases, but the protein levels are maintained at high levels. Significantly, the α-Syn protein level increases with aging in human substantia nigra. Pulse-chase analyses of α-Syn half-lives in neurons and neuronal cell lines indicate that, in mature neurons, the expression of α-Syn is regulated by the post-translational stabilization of α-Syn protein. Moreover, A53T mutant human α-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 α-Syn protein in neuronal cells. Because increased stabilization of α-Syn protein is associated with increased protein levels and accumulation of pathogenic protein modifications, such as oxidative damage, the stabilization of α-Syn with aging may be a significant factor in the pathogenesis of α-synucleinopathies.

Original languageEnglish (US)
Pages (from-to)7400-7409
Number of pages10
JournalJournal of Neuroscience
Volume24
Issue number33
DOIs
StatePublished - Aug 18 2004

Fingerprint

Synucleins
Parkinson Disease
Mutation
Proteins
Neurons
Cell Line
Substantia Nigra
Mutant Proteins
Transgenic Mice
Messenger RNA
Brain

Keywords

  • Aging
  • Metabolism
  • Oxidative stress
  • Parkinson's disease
  • Synuclein
  • Synucleinopathy

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Stabilization of α-synuclein protein with aging and familial Parkinson's disease-linked A53T mutation. / Li, Wenxue; Lesuisse, Christian; Xu, Yanqun; Troncoso, Juan C; Price, Donald L.; Lee, Michael K.

In: Journal of Neuroscience, Vol. 24, No. 33, 18.08.2004, p. 7400-7409.

Research output: Contribution to journalArticle

Li, Wenxue ; Lesuisse, Christian ; Xu, Yanqun ; Troncoso, Juan C ; Price, Donald L. ; Lee, Michael K. / Stabilization of α-synuclein protein with aging and familial Parkinson's disease-linked A53T mutation. In: Journal of Neuroscience. 2004 ; Vol. 24, No. 33. pp. 7400-7409.
@article{9e361465d0a742febe854d620198026f,
title = "Stabilization of α-synuclein protein with aging and familial Parkinson's disease-linked A53T mutation",
abstract = "We examined the potential relationship between aging and α-synuclein (α-Syn) metabolism, both of which are implicated in the pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies. During aging, α-Syn and β-Syn mRNA expression in brain decreases, but the protein levels are maintained at high levels. Significantly, the α-Syn protein level increases with aging in human substantia nigra. Pulse-chase analyses of α-Syn half-lives in neurons and neuronal cell lines indicate that, in mature neurons, the expression of α-Syn is regulated by the post-translational stabilization of α-Syn protein. Moreover, A53T mutant human α-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 α-Syn protein in neuronal cells. Because increased stabilization of α-Syn protein is associated with increased protein levels and accumulation of pathogenic protein modifications, such as oxidative damage, the stabilization of α-Syn with aging may be a significant factor in the pathogenesis of α-synucleinopathies.",
keywords = "Aging, Metabolism, Oxidative stress, Parkinson's disease, Synuclein, Synucleinopathy",
author = "Wenxue Li and Christian Lesuisse and Yanqun Xu and Troncoso, {Juan C} and Price, {Donald L.} and Lee, {Michael K.}",
year = "2004",
month = "8",
day = "18",
doi = "10.1523/JNEUROSCI.1370-04.2004",
language = "English (US)",
volume = "24",
pages = "7400--7409",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "33",

}

TY - JOUR

T1 - Stabilization of α-synuclein protein with aging and familial Parkinson's disease-linked A53T mutation

AU - Li, Wenxue

AU - Lesuisse, Christian

AU - Xu, Yanqun

AU - Troncoso, Juan C

AU - Price, Donald L.

AU - Lee, Michael K.

PY - 2004/8/18

Y1 - 2004/8/18

N2 - We examined the potential relationship between aging and α-synuclein (α-Syn) metabolism, both of which are implicated in the pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies. During aging, α-Syn and β-Syn mRNA expression in brain decreases, but the protein levels are maintained at high levels. Significantly, the α-Syn protein level increases with aging in human substantia nigra. Pulse-chase analyses of α-Syn half-lives in neurons and neuronal cell lines indicate that, in mature neurons, the expression of α-Syn is regulated by the post-translational stabilization of α-Syn protein. Moreover, A53T mutant human α-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 α-Syn protein in neuronal cells. Because increased stabilization of α-Syn protein is associated with increased protein levels and accumulation of pathogenic protein modifications, such as oxidative damage, the stabilization of α-Syn with aging may be a significant factor in the pathogenesis of α-synucleinopathies.

AB - We examined the potential relationship between aging and α-synuclein (α-Syn) metabolism, both of which are implicated in the pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies. During aging, α-Syn and β-Syn mRNA expression in brain decreases, but the protein levels are maintained at high levels. Significantly, the α-Syn protein level increases with aging in human substantia nigra. Pulse-chase analyses of α-Syn half-lives in neurons and neuronal cell lines indicate that, in mature neurons, the expression of α-Syn is regulated by the post-translational stabilization of α-Syn protein. Moreover, A53T mutant human α-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 α-Syn protein in neuronal cells. Because increased stabilization of α-Syn protein is associated with increased protein levels and accumulation of pathogenic protein modifications, such as oxidative damage, the stabilization of α-Syn with aging may be a significant factor in the pathogenesis of α-synucleinopathies.

KW - Aging

KW - Metabolism

KW - Oxidative stress

KW - Parkinson's disease

KW - Synuclein

KW - Synucleinopathy

UR - http://www.scopus.com/inward/record.url?scp=7244243876&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=7244243876&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.1370-04.2004

DO - 10.1523/JNEUROSCI.1370-04.2004

M3 - Article

C2 - 15317865

AN - SCOPUS:7244243876

VL - 24

SP - 7400

EP - 7409

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 33

ER -