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Mov Disord. 2019 Sep 4. doi: 10.1002/mds.27823. [Epub ahead of print]

Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

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Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Philadelphia, Pennsylvania, USA.
Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, Hess Research Center 9th Floor, New York, New York, USA.
CNS Research Group, Department of Pharmacology and Physiology, Department of Neurosciences, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
University of British Columbia and Vancouver Coastal Health, Pacific Parkinson's Research Centre & National Parkinson Foundation Centre of Excellence, Vancouver, BC, Canada.
Department of Neurology, Philipps University Marburg, Marburg, Germany.
HM CINAC, HM Puerta del Sur, Hospitales de Madrid, Mostoles Medical School, CEU-San Pablo University, and CIBERNED, Instituto Carlos III, Madrid, Spain.
Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA.


While current effective therapies are available for the symptomatic control of PD, treatments to halt the progressive neurodegeneration still do not exist. Loss of dopamine neurons in the SNc and dopamine terminals in the striatum drive the motor features of PD. Multiple lines of research point to several pathways which may contribute to dopaminergic neurodegeneration. These pathways include extensive axonal arborization, mitochondrial dysfunction, dopamine's biochemical properties, abnormal protein accumulation of α-synuclein, defective autophagy and lysosomal degradation, and synaptic impairment. Thus, understanding the essential features and mechanisms of dopaminergic neuronal vulnerability is a major scientific challenge and highlights an outstanding need for fostering effective therapies against neurodegeneration in PD. This article, which arose from the Movement Disorders 2018 Conference, discusses and reviews the possible mechanisms underlying neuronal vulnerability and potential therapeutic approaches in PD.


Parkinson; dopamine; substantia nigra; synaptic; synuclein


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