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Review
. 2019 Oct;34(10):1406-1422.
doi: 10.1002/mds.27823. Epub 2019 Sep 4.

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

Yvette C Wong  1 , Kelvin Luk  2 , Kerry Purtell  3 , Samuel Burke Nanni  4 , A Jon Stoessl  5 , Louis-Eric Trudeau  4 , Zhenyu Yue  3 , Dimitri Krainc  1 , Wolfgang Oertel  6 , Jose A Obeso  7 , Laura A Volpicelli-Daley  8
Affiliations
Review

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

Yvette C Wong et al. Mov Disord. 2019 Oct.

Abstract

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. © 2019 International Parkinson and Movement Disorder Society.

Keywords: Parkinson; dopamine; substantia nigra; synaptic; synuclein.

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Figures

Figure 1.
Figure 1.. Role of oxidized dopamine in dopaminergic neuronal selective vulnerability.
Dopamine is normally generated from tyrosine and L-DOPA. It subsequently becomes incorporated into synaptic vesicles via VMAT2 and is finally released upon synaptic vesicle exocytosis. In PD dopaminergic patient neurons: 1) increased oxidation of cytosolic dopamine leads to generation of oxidized dopamine which can contribute to downstream mitochondrial and lysosomal dysfunction, increased α-synuclein oligomerization, and decreased lysosomal GBA1 enzyme activity; and 2) defective synaptic vesicle endocytosis contributes to inefficient synaptic vesicle recycling and increased cytosolic dopamine available for oxidation.
Figure 2.
Figure 2.. Parkinson’s disease genes function at the intersection of synaptic vesicle endo/exocytosis and autophagy at the synapse.
EndophilinA1 (EndoA) binds endocytosed vesicles and is responsible for recruiting the 5’-phosphatase synaptojanin1 (SynJ1), which together with auxilin, removes the clathrin coat so that vesicles can be recycled. Phosphorylation of auxilin and Synj1 by LRRK2 disrupts interactions with clathrin and EndoA, respectively. LRRK2 phosphorylation promotes the association of EndoA with highly-curved autophagosome membranes, where it recruits PI(3)P-binding proteins involved in autophagosome formation, such as WIPI2. SynJ1 converts PI(3)P to PI on the autophagosome membrane, which allows for dissociation of WIPI2 and maturation of autophagosomes, which are then trafficked back to the cell body for degradation. Parkin is also thought to regulate EndoA and SynJ1 activity through ubiquitination, although the functional consequence is not yet clear.
Figure 3.
Figure 3.. Contributors to neuronal vulnerability in Parkinson’s disease.
Dopaminergic neurons in the SNpc which project to the striatum degenerate in PD. Multiple factors contribute to this neuronal vulnerability including: 1) extensive axonal arborization; 2) mitochondrial dysfunction due to damaged mitochondria: 3) dopamine’s biochemical properties including increased oxidized dopamine: 4) abnormal protein accumulation of α-synuclein: 5) defective autophagy and lysosomal degradation: and 6) synaptic vesicle defects.
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