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Cited by 110Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingNeurological disorders and treatments

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

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Gcwensa, Nolwazi Z., Russell, Drèson L., Cowell, Rita M., Volpicelli-Daley, Laura A.·2021·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2021.626128PMC PMC7960781
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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.

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  • Neuritic and axonal degeneration is one of the earliest pathological features of PD.

    “As neuritic and axonal degeneration is one of the earliest pathological features of PD [221], inhibition of RhoA signaling might be a promising strategy for early disease intervention.”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [221]

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Cited by

Sorted by citations

Authors
Gcwensa, N. Z., Russell, D. L., Cowell, R. M., & Volpicelli-Daley, L. A.
Affiliations
Civitan International (US)
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2021-03-02
Volume
15
Pages
626128-626128
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2021.626128
PMC
PMC7960781
OpenAlex
W3135528648
Cited by
110
References
12
Citations by year
2026: 19 · 2025: 24 · 2024: 29 · 2023: 23 · 2022: 12 · 2021: 3
FWCI
8.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Neurological Disorders and Stroke
  • Michael J. Fox Foundation for Parkinson’s Research
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Neurology › Neurological disorders and treatments
Keywords
Parkinson's disease, synaptic dysfunction, axonal degeneration, presynaptic terminals, dopaminergic neurons, substantia nigra pars compacta, striatum, SNCA, cholinergic neurons, excitatory synapses

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