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Lysosome-dependent pathways as a unifying theme in Parkinson's disease§

Authors

  • George K. Tofaris PhD, MRCP

    Corresponding author
    1. Nuffield Department of Clinical Neurosciences and Oxford Parkinson's Disease Center, University of Oxford, Oxford, United Kingdom
    • Nuffield Department of Clinical Neurosciences and Oxford Parkinson's Disease Center, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK
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  • Funding agencies: The author is supported by a Wellcome Trust Intermediate Clinical Fellowship and Parkinson's UK.

  • Relevant conflicts of interest/financial disclosures: Nothing to report.

  • §

    Full financial disclosures and author roles may be found in the online version of this artcle.

Abstract

Although the pathogenesis of Parkinson's disease (PD) is considered multifactorial, evidence from genetics and cell biology has implicated specific molecular pathways. This article summarizes evidence that suggests that the level of intracellular alpha-synuclein is critical for the onset of neurodegeneration with Lewy bodies and dependent, to a large extent, on lysosomal degradation. The function of other key proteins that emerged from genetics is discussed: Pink1 and Parkin regulate the degradation of damaged mitochondria by the lysosome (mitophagy). Glucocerebrosidase and ATP13A2 are important components of this degradative organelle. VPS35 and LRRK2 may regulate trafficking within lysosome-dependent pathways, such as autophagy and endosomal vesicle recycling. Clinically, diffuse alpha-synucleinopathy or dementia seems to correlate with mutations which interfere with the broader function of lysosomal pathways, whereas a predominantly motor syndrome and nigrostriatal degeneration is associated with specific defects in mitophagy. Based on these studies, it is proposed that a protein network involved in trafficking to, or degradation by, lysosomes could be sufficient to explain the phenotypic spectrum within PD in a unifying biochemical pathway. © 2012 Movement Disorder Society

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