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The Journal of Neuroscience, August 18, 2004, 24(33):7400-7409; doi:10.1523/JNEUROSCI.1370-04.2004

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Cellular/Molecular
Stabilization of -Synuclein Protein with Aging and Familial Parkinson's Disease-Linked A53T Mutation

Wenxue Li,¹ Christian Lesuisse,¹ Yanqun Xu,¹ Juan C. Troncoso,^1,4 Donald L. Price,^1,2,3,4 and Michael K. Lee^1,4

Departments of ¹Pathology, ²Neurology, and ³Neuroscience, ⁴Johns Hopkins Udall Parkinson's Disease Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

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

Key words: synuclein; Parkinson's disease; aging; metabolism; oxidative stress; synucleinopathy

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Received April 12, 2004; revised July 13, 2004; accepted July 15, 2004.

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