Wild Type α-Synuclein Is Degraded by Chaperone-mediated Autophagy and Macroautophagy in Neuronal CellsS
α-Synuclein (ASYN) is crucial in Parkinson disease (PD) pathogenesis. Increased levels of wild type (WT) ASYN expression are sufficient to cause PD in humans. The manner of post-transcriptional regulation of ASYN levels is controversial. Previously, we had shown that WT ASYN can be degraded by chape...
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Veröffentlicht in: | The Journal of biological chemistry 2008-08, Vol.283 (35), p.23542-23556 |
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Zusammenfassung: | α-Synuclein (ASYN) is crucial in Parkinson disease (PD) pathogenesis.
Increased levels of wild type (WT) ASYN expression are sufficient to cause PD
in humans. The manner of post-transcriptional regulation of ASYN levels is
controversial. Previously, we had shown that WT ASYN can be degraded by
chaperone-mediated autophagy (CMA) in isolated liver lysosomes. Whether this
occurs in a cellular and, in particular, in a neuronal cell context is
unclear. Using a mutant ASYN form that lacks the CMA recognition motif and RNA
interference against the rate-limiting step in the CMA pathway, Lamp2a, we
show here that CMA is indeed involved in WT ASYN degradation in PC12 and
SH-SY5Y cells, and in primary cortical and midbrain neurons. However, the
extent of involvement varies between cell types, potentially because of
differences in compensatory mechanisms. CMA inhibition leads to an
accumulation of soluble high molecular weight and detergent-insoluble species
of ASYN, suggesting that CMA dysfunction may play a role in the generation of
such aberrant species in PD. ASYN and Lamp2a are developmentally regulated in
parallel in cortical neuron cultures and
in vivo
in the central
nervous system, and they physically interact as indicated by
co-immunoprecipitation. In contrast to previous reports, inhibition of
macroautophagy, but not the proteasome, also leads to WT ASYN accumulation,
suggesting that this lysosomal pathway is also involved in normal ASYN
turnover. These results indicate that CMA and macroautophagy are important
pathways for WT ASYN degradation in neurons and underline the importance of
CMA as degradation machinery in the nervous system. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M801992200 |