Journal
JOURNAL OF NEUROSCIENCE
Volume 21, Issue 24, Pages 9549-9560Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.21-24-09549.2001
Keywords
Parkinson's disease; Lewy body; ubiquitin; autophagy; proteasome; lysosome; dopamine
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alpha -Synuclein mutations have been identified in certain families with Parkinson's disease (PD), and alpha -synuclein is a major component of Lewy bodies. Other genetic data indicate that the ubiquitin-dependent proteolytic system is involved in PD pathogenesis. We have generated stable PC12 cell lines expressing wild-type or A53T mutant human alpha -synuclein. Lines expressing mutant but not wild-type alpha -synuclein show: (1) disruption of the ubiquitin-dependent proteolytic system, manifested by small cytoplasmic ubiquitinated aggregates and by an increase in polyubiquitinated proteins; (2) enhanced baseline nonapoptotic death; (3) marked accumulation of autophagic-vesicular structures; (4) impairment of lysosomal hydrolysis and proteasomal function; and (5) loss of catecholamine-secreting dense core granules and an absence of depolarization-induced dopamine release. Such findings raise the possibility that the primary abnormality in these cells may involve one or more deficits in the lysosomal and/or proteasomal degradation pathways, which in turn lead to loss of dopaminergic capacity and, ultimately, to death. These cells may serve as a model to study the effects of aberrant alpha -synuclein on dopaminergic cell function and survival.
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