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The Journal of Neuroscience, December 15, 2001, 21(24):9549-9560
Expression of A53T Mutant But Not Wild-Type  -Synuclein in PC12
Cells Induces Alterations of the Ubiquitin-Dependent Degradation
System, Loss of Dopamine Release, and Autophagic Cell Death
Leonidas
Stefanis1, 2,
Kristin E.
Larsen2,
Hardy
J.
Rideout2,
David
Sulzer2, 3, and
Lloyd A.
Greene1
Departments of 1 Pathology, 2 Neurology,
and 3 Psychiatry, Columbia University, New York, New
York 10032
 -Synuclein mutations have been identified in certain families
with Parkinson's disease (PD), and -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 -synuclein. Lines expressing mutant but not wild-type
-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 -synuclein on dopaminergic cell function and survival.
Key words:
Parkinson's disease; Lewy body; ubiquitin; autophagy; proteasome; lysosome; dopamine
Copyright © 2001 Society for Neuroscience 0270-6474/01/21249549-12$05.00/0
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