Does Impairment of the Ubiquitin-Proteasome System or the Autophagy-Lysosome Pathway Predispose Individuals to Neurodegenerative Disorders such as Parkinson's Disease?
Issue title: Similarities and Differences Between Mild Cognitive Impairment and Alzheimer's Disease
Affiliations: Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan | Sanders-Brown Center on Aging and Alzheimer's Disease Center, Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA
Correspondence:
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Corresponding author: Keiji Tanaka, Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. Tel.: +81 3 5316 3337; Fax: +81 3 5316 3198; E-mail: tanaka-kj@igakuken.or.jp.
Abstract: About twenty years ago, an abnormal enrichment of ubiquitin in the inclusion bodies of various neurodegenerative disorders was reported. To date, this phenotype has been a diagnostic feature of many neurodegenerative disorders including Alzheimer's and Parkinson's diseases (PD). Because ubiquitin tags proteins that must be eliminated from cells, thereby targeting them for proteasomal degradation, many scientists believed that the ubiquitin-proteasome system (UPS) was inactivated in these neurodegenerative disorders. This inactivation would lead to an accumulation of ubiquitylated proteins with their concomitant aggregation into inclusion bodies and subsequent neuronal death. This hypothesis was further fuelled by the discovery that parkin, the causal gene of autosomal recessive juvenile Parkinsonism, functions as a ubiquitin ligase. However, recent findings by several groups demonstrated that ubiquitylation is also relevant to the autophagy system, with parkin promoting autophagy of dysfunctional mitochondria following the loss of mitochondrial membrane potential. These novel topics do not necessarily mean that the proteasome is involved in neurodegeneration of PD. In this review, we describe current evidence and controversies regarding the relationship between UPS and neurodegenerative disorders such as PD, and discuss several scientific discrepancies that await further clarification.
