The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease.
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 alpha-synuclein and the increase of intracellular concentrations of non-mutant alpha-synuclein have been associated with Parkinson's disease phenotype. The demonstration that alpha-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 alpha-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.
Pan
Tianhong
T
Parkinson's Disease Research Laboratory, Baylor College of Medicine, Houston, TX 77030, USA.
Kondo
Seiji
S
Le
Weidong
W
Jankovic
Joseph
J
D001343:Autophagy / Q000502:physiology*; D006801:Humans; D008247:Lysosomes / Q000502:physiology*; D009154:Mutation; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000235:genetics; D010300:Parkinson Disease / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D025801:Ubiquitin / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics
D009419:Nerve Tissue Proteins; D025801:Ubiquitin; D051844:alpha-Synuclein; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases