Lysosomal degradation of α-synuclein in vivo

Sally K. Mak, Alison L. McCormack, Amy B. Manning-Bog, Ana Maria Cuervo, Donato A. Di Monte

206 Scopus citations

Abstract

Pathologic accumulation of α-synuclein is a feature of human parkinsonism and other neurodegenerative diseases. This accumulation may be counteracted by mechanisms of protein degradation that have been investigated in vitro but remain to be elucidated in animal models. In this study, lysosomal clearance of α-synuclein in vivo was indicated by the detection of α-synuclein in the lumen of lysosomes isolated from the mouse midbrain. When neuronal α-synuclein expression was enhanced as a result of toxic injury (i.e. treatment of mice with the herbicide paraquat) or transgenic protein overexpression, the intralysosomal content of α-synuclein was also significantly increased. This effect was paralleled by a marked elevation of the lysosome-associated membrane protein type 2A (LAMP-2A) and the lysosomal heat shock cognate protein of 70 kDa (hsc70), two essential components of chaperone-mediated autophagy (CMA). Immunofluorescence microscopy revealed an increase in punctate (lysosomal) LAMP-2A staining that co-localized with α-synuclein within nigral dopaminergic neurons of paraquat-treated and α-synuclein-overexpressing animals. The data provide in vivo evidence of lysosomal degradation of α-synuclein under normal conditions and, quite importantly, under conditions of enhanced protein burden. In the latter, increased lysosomal clearance of α-synuclein was mediated, at least in part, by CMA induction. It is conceivable that these neuronal mechanisms of protein clearance play an important role in neurodegenerative processes characterized by abnormal α-synuclein buildup.

Original languageEnglish (US)
Pages (from-to)13621-13629
Number of pages9
JournalJournal of Biological Chemistry
Volume285
Issue number18
DOIs
StatePublished - Apr 30 2010

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lysosomal degradation of α-synuclein in vivo. / Mak, Sally K.; McCormack, Alison L.; Manning-Bog, Amy B.; Cuervo, Ana Maria; Di Monte, Donato A.

In: Journal of Biological Chemistry, Vol. 285, No. 18, 30.04.2010, p. 13621-13629.

Research output: Contribution to journalArticle