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. 2021 Mar 2:15:626128.
doi: 10.3389/fncel.2021.626128. eCollection 2021.

Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson's Disease

Nolwazi Z Gcwensa  1 , Drèson L Russell  1 , Rita M Cowell  2 , Laura A Volpicelli-Daley  1
Affiliations

Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson's Disease

Nolwazi Z Gcwensa et al. Front Cell Neurosci. .

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disease that impairs movement as well as causing multiple other symptoms such as autonomic dysfunction, rapid eye movement (REM) sleep behavior disorder, hyposmia, and cognitive changes. Loss of dopamine neurons in the substantia nigra pars compacta (SNc) and loss of dopamine terminals in the striatum contribute to characteristic motor features. Although therapies ease the symptoms of PD, there are no treatments to slow its progression. Accumulating evidence suggests that synaptic impairments and axonal degeneration precede neuronal cell body loss. Early synaptic changes may be a target to prevent disease onset and slow progression. Imaging of PD patients with radioligands, post-mortem pathologic studies in sporadic PD patients, and animal models of PD demonstrate abnormalities in presynaptic terminals as well as postsynaptic dendritic spines. Dopaminergic and excitatory synapses are substantially reduced in PD, and whether other neuronal subtypes show synaptic defects remains relatively unexplored. Genetic studies implicate several genes that play a role at the synapse, providing additional support for synaptic dysfunction in PD. In this review article we: (1) provide evidence for synaptic defects occurring in PD before neuron death; (2) describe the main genes implicated in PD that could contribute to synapse dysfunction; and (3) show correlations between the expression of Snca mRNA and mouse homologs of PD GWAS genes demonstrating selective enrichment of Snca and synaptic genes in dopaminergic, excitatory and cholinergic neurons. Altogether, these findings highlight the need for novel therapeutics targeting the synapse and suggest that future studies should explore the roles for PD-implicated genes across multiple neuron types and circuits.

Keywords: Dementia with Lewy Bodies; GWAS; Parkinson’s disease; degeneration; synapse; α-synuclein.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Adapted from Froula et al. (2018). All experiments were performed in primary hippocampal neurons exposed to fibrils (or control) and analyzed 7 days later. (A) α-synuclein (green) colocalizes with vGLUT1 (red) at presynaptic terminals in excitatory neurons, but not vGAT (red) at presynaptic terminals in inhibitory neurons. (B) Neurons were transfected with LifeAct-GFP. There is a significant reduction in mushroom excitatory spine densities in neurons with α-synuclein inclusions, but not in α-synuclein knockout neurons exposed to fibrils. (C) At 7 days following fibril addition to neurons there is no neuron death. (D–G) Recording of mEPSCs shows increased mEPSC frequency, but not increased mEPSC amplitudes. (H) Electron microscopy of presynaptic terminals shows increased synaptic vesicle docking.*p < 0.05; **p < 0.01; ***p < 0.001.
Figure 2
Figure 2
Adapted from West et al. (2014). Leucine-rich repeat kinase 2 (LRRK2) (red) is highly expressed in layer IV/V pyramidal neurons in the mouse motor cortex.
Figure 3
Figure 3
Comparison of neuroanatomical location of Snca and other Parkinson’s disease (PD) implicated genes using single-cell transcriptional data in the mouse brain. Correlation analyses of single-cell transcriptional abundance data was performed between Snca and genes implicated by PD GWAS; genes with significant correlations to Snca across nine regions and > 500 distinct cell subclusters (Saunders et al., 2018) are listed (two-tailed t-test; (A) GWAS genes in red, PARK homologs in blue). Plotting individual subcluster values for Snca vs. Sh3gl2 (B) Synj1 (C) and Lrrk2 (D) reveals neuron types which co-express those transcripts. Abundance values for each transcript by cell type are displayed in panel (E) and compared across different regions in panel (F). (E) Kruskal–Wallis analysis, followed by multiple comparisons. a: different than all except GABAergic-PV, p < 0.05; b: different than all except DAergic–not midbrain and non-neurons, p < 0.05; c: different than all except dopaminergic–not midbrain, p < 0.05, d: different than all others, p < 0.05. (F) two-way ANOVA by region, Tukey’s post hoc; e: all different from each other, p < 0.05; f: all different except Snca vs. Synj1; g: all different except Sh3gl2 vs. Lrrk2, h: all different except Snca vs. Sh3gl2; p < 0.05. *p < 0.05, **p < 0.01, ****p < 0.0001.
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