The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease

Tianhong Pan, Seiji Kondo, Weidong Le, Joseph Jankovic

Research output: Contribution to journalReview articlepeer-review

410 Scopus citations

Abstract

The ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) are the two most important mechanisms that normally repair or remove abnormal proteins. Alterations in the function of these systems to degrade misfolded and aggregated proteins are being increasingly recognized as playing a pivotal role in the pathogenesis of many neurodegenerative disorders such as Parkinson's disease. Dysfunction of the UPS has been already strongly implicated in the pathogenesis of this disease and, more recently, growing interest has been shown in identifying the role of ALP in neurodegeneration. Mutations of α-synuclein and the increase of intracellular concentrations of non-mutant α-synuclein have been associated with Parkinson's disease phenotype. The demonstration that α-synuclein is degraded by both proteasome and autophagy indicates a possible linkage between the dysfunction of the UPS or ALP and the occurrence of this disorder. The fact that mutant α-synucleins inhibit ALP functioning by tightly binding to the receptor on the lysosomal membrane for autophagy pathway further supports the assumption that impairment of the ALP may be related to the development of Parkinson's disease. In this review, we summarize the recent findings related to this topic and discuss the unique role of the ALP in this neurogenerative disorder and the putative therapeutic potential through ALP enhancement.

Original languageEnglish (US)
Pages (from-to)1969-1978
Number of pages10
JournalBrain
Volume131
Issue number8
DOIs
StatePublished - Aug 2008

Keywords

  • Autophagy-lysosome pathway
  • Neurodegenerative disease
  • Neuroprotection
  • Parkinson's disease
  • Ubiquitin-proteasome system

ASJC Scopus subject areas

  • Neuroscience(all)

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