Article type: Narrative Review
Article title: Alpha-Synuclein Neurobiology in Parkinson’s Disease: A Comprehensive Review of Its Role, Mechanisms, and Therapeutic Perspectives
Journal: Brain Sciences
Year: 2025
Authors: Jamir Pitton Rissardo, Andrew McGarry, Yiwen Shi, Ana Leticia Fornari Caprara, and George T. Kannarkat
E-mail: jamirrissardo@gmail.com
ABSTRACT
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and the presence of intracellular α-synuclein (αSyn) aggregates known as Lewy bodies (LB). αSyn, a presynaptic protein, is believed to play a crucial role in synaptic function, neurotransmitter release, and neuronal plasticity. However, its misfolding and aggregation are thought to be central to PD pathogenesis. This review provides a comprehensive analysis of αSyn’s role in PD, exploring its normal physiological functions, pathological mechanisms, and therapeutic potential. The pathological transformation of αSyn involves structural alterations that promote oligomerization and fibrillization, leading to toxic gain-of-function effects. These aggregates disrupt cellular homeostasis through mechanisms including mitochondrial dysfunction, oxidative stress, lysosomal impairment, and endoplasmic reticulum stress. Furthermore, pathogenic αSyn is thought to exacerbate neurodegeneration via prion-like spread along interconnected neuronal circuits. Emerging evidence highlights the frequent co-occurrence of other proteinopathies, such as tau and amyloid-β, which may synergistically accelerate disease progression. Targeting αSyn has emerged as a potential therapeutic strategy. Approaches such as immunotherapy, small-molecule inhibitors, gene silencing, and modulation of protein degradation pathways (e.g., autophagy and proteasomal systems) are actively being explored. Additionally, lifestyle-based interventions, particularly exercise, have shown neuroprotective effects, potentially mediated by irisin—a myokine implicated in protein clearance and synaptic resilience—underscoring the importance of multimodal strategies in PD management.
Keywords: synucleinopathy; co-pathology; neurodegeneration; immunotherapy; biomarkers; prion-like spread.
Full text available at:
DOI
Citation
Pitton Rissardo J, McGarry A, Shi Y, Fornari Caprara AL, Kannarkat GT. Alpha-Synuclein Neurobiology in Parkinson’s Disease: A Comprehensive Review of Its Role, Mechanisms, and Therapeutic Perspectives. Brain Sci 2025;15:1260. https://doi.org/10.3390/brainsci15121260
Figure 1. Structure of αSyn. In the figure are represented the domains, amino acid sequence, missense mutations, and major post-translational modifications sites of αSyn. Abbreviations: A, acetylation; N, nitration; P, phosphorylation; S, SUMOylation; U, ubiquitination; G, O-GlcNAcylation.
Figure 2. Schematic representation of a neuron highlighting major cellular dysfunctions implicated by pathogenic αSyn. Mutant αSyn promotes misfolding and aggregation into oligomers and fibrils, triggering prion-like propagation across neurons. These aggregates impair synaptic vesicle trafficking and mitochondrial function, disrupt endoplasmic reticulum homeostasis, and interfere with axonal transport. Additionally, αSyn mutations compromise protein clearance mechanisms, including chaperone-mediated autophagy and the ubiquitin–proteasome system, while activating neuroinflammatory cascades through microglial and astrocytic signaling. Collectively, these alterations converge to induce oxidative stress, calcium dysregulation, and neuronal death, highlighting the multifactorial nature of αSyn-driven neurodegeneration.
Figure 3. Schematic representation of proposed αSyn propagation pathways from peripheral organs to the brain. Illustrated are three hypothesized routes by which misfolded αSyn may ascend from peripheral sites to central nervous system structures. Nasal–brain axis: αSyn enters via the olfactory epithelium, propagates through the olfactory bulb and limbic system, and may reach brainstem autonomic centers via multisynaptic connections through the hypothalamus. Kidney–brain axis: aggregates may travel via sympathetic fibers originating in the renal plexus, ascending through the spinal cord to brainstem nuclei. Gut–brain axis: αSyn spreads from the enteric nervous system via the vagus nerve to the dorsal motor nucleus of the vagus (DMV). Arrows indicate proposed directions of propagation.
Figure 4. Tau, amyloid-β, αSyn, and TDP-43 proteinopathies. AD, Alzheimer’s disease; AGD, argyrophilic grain disease; ALS, amyotrophic lateral sclerosis; bvFTD, behavioral variant frontotemporal dementia; CAA, cerebral amyloid angiopathy; CBD, corticobasal degeneration; CJD, Creutzfeldt-Jakob disease; CTE, chronic traumatic encephalopathy; DS, Down syndrome; FFI, fatal familial insomnia; FTLD, frontotemporal lobar degeneration; GVD, granulovacuolar degeneration; GSS, Gerstmann-Sträussler-Scheinker; HD, Huntington’s disease; LATE, limbic-predominant age-related TDP-43 encephalopathy; LBD, Lewy body dementia; MND-TFD, frontotemporal dementia with motor neuron disease; MSA, multiple system atrophy; PD, Parkinson’s disease; PDD, Parkinson’s disease dementia; PiD, Pick’s disease; PSP, progressive supranuclear palsy; sCJD, sporadic Creutzfeldt-Jakob disease; svPPA, semantic variant primary progressive aphasia; VPSPr, variably protease-sensitive prionopathy.
Table 1. Allelic Variants of αSyn in PD.
Table 2. Effect on αSyn and post-translational modifications.
Table 3. Pathological and Motor Phenotypic Characteristics of αSyn Mouse Models.
Table 5. αSyn-Targeted Disease-Modifying Therapies for PD in Clinical Trials Registered in the ClinicalTrials.gov Database.