α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges

Abstract

Parkinson's disease and related synucleinopathies, including dementia with Lewy bodies and multiple system atrophy, are characterised by the pathological aggregation of the α-synuclein (aSyn) protein in neuronal and glial cells, leading to cellular dysfunction and neurodegeneration. This review synthesizes knowledge of aSyn biology, including its structure, aggregation mechanisms, cellular interactions, and systemic influences. We highlight the structural diversity of aSyn aggregates, ranging from oligomers to fibrils, their strain-like properties, and their prion-like propagation. While the role of prion-like mechanisms in disease progression remains a topic of ongoing debate, these processes may contribute to the clinical heterogeneity of synucleinopathies. Dysregulation of protein clearance pathways, including chaperone-mediated autophagy and the ubiquitin-proteasome system, exacerbates aSyn accumulation, while post-translational modifications influence its toxicity and aggregation propensity. Emerging evidence suggests that immune responses and alterations in the gut microbiome are key modulators of aSyn pathology, linking peripheral processes-particularly those of intestinal origin-to central neurodegeneration. Advances in biomarker development, such as cerebrospinal fluid assays, post-translationally modified aSyn, and real-time quaking-induced conversion technology, hold promise for early diagnosis and disease monitoring. Furthermore, positron emission tomography imaging and conformation-specific antibodies offer innovative tools for visualising and targeting aSyn pathology in vivo. Despite significant progress, challenges remain in accurately modelling human synucleinopathies, as existing animal and cellular models capture only specific aspects of the disease. This review underscores the need for more reliable aSyn biomarkers to facilitate the development of effective treatments. Achieving this goal requires an interdisciplinary approach integrating genetic, epigenetic, and environmental insights.

Keywords: Parkinson’s disease; alpha-synuclein; biomarkers; neurodegeneration; protein aggregation; synucleinopathies.

Figure 1

Structural dynamics, molecular interactions, and pathological roles of alpha-synuclein. Structural states of alpha-synuclein. Alpha-synuclein exists in multiple conformations, including monomeric intrinsically disordered forms, membrane-bound α-helical structures, and aggregated fibrillar states, with its aggregation influenced by post-translational modifications (PTMs), pH, temperature, and lipid interactions. Molecular interactome. Alpha-synuclein interacts with a diverse range of molecular partners, including lipid membranes, SNARE proteins, cytoskeletal components, vesicular trafficking machinery, and organelles, modulating its physiological functions and pathological effects. Physiological functions and localization. Alpha-synuclein plays a crucial role in synaptic vesicle trafficking, neurotransmitter release, calcium homeostasis, ATP synthesis, and nuclear processes, including transcription regulation and DNA repair. Genetic and phenotypic diversity in synucleinopathies. Mutations, duplications, and triplications in SNCA, along with environmental and epigenetic factors, contribute to the aggregation and neurotoxicity of alpha-synuclein, underlying the pathogenesis of Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies.

Figure 2

Alpha-synuclein aggregation, post-translational modifications, and degradation pathways. Alpha-synuclein misfolds and progressively assembles into soluble oligomers and prefibrillar aggregates, which may evolve into fibrils composed of protofibrillar subdomains *. Post-translational modifications modulate aggregation propensity, while clearance mechanisms such as chaperone-mediated autophagy and the ubiquitin–proteasome system regulate accumulation, with phosphorylation at serine-129 as a key pathological marker. Alpha-synuclein inclusions co-localize with synphilin-1, Parkin, tau, molecular chaperones, LRRK2, ubiquitin, and cytoskeletal proteins, contributing to neurodegeneration. The ubiquitin–proteasome system mediates clearance of alpha-synuclein aggregates and chaperone-mediated autophagy, with dysfunction in these pathways leading to its accumulation, particularly in the substantia nigra.

Figure 3

Propagation and cellular interactions of alpha-synuclein pathology. Alpha-synuclein aggregates propagate between neurons through anterograde transport, exocytosis, endocytosis, and seeding mechanisms, thereby contributing to the spread of disease across brain regions. Microglia play a crucial role in alpha-synuclein clearance, but their activation may also exacerbate neuroinflammation. In multiple system atrophy (MSA), oligodendrocytes harbour alpha-synuclein inclusions, further driving disease pathology. The gut–brain axis is implicated in early alpha-synuclein aggregation, with enteric glial cells, increased gut permeability, and dysbiosis influencing neurodegenerative processes. Transmission via the vagus nerve has been proposed as a route for gut-derived alpha-synuclein pathology to reach the central nervous system, highlighting a potential mechanism for disease initiation and progression.

Figure 4

Challenges and future perspectives in synucleinopathy diagnostics and therapeutics. Early diagnosis of synucleinopathies relies on the detection of alpha-synuclein biomarkers in cerebrospinal fluid, saliva, plasma, and tear fluid using techniques such as mass spectrometry, antibody-based detection, and real-time quaking-induced conversion (RT-QuIC). However, challenges remain in assay sensitivity, standardisation, and optimising methods for aggregation detection. Imaging approaches are further limited by blood–brain barrier penetration. Therapeutic strategies, including antibody-based therapies, face hurdles related to specificity, immunogenicity, pharmacokinetics, and pharmacodynamics. Future perspectives involve the development of humanized antibodies, advanced cryo-electron microscopy (cryo-EM) and mass spectrometry techniques for antibody refinement, and the use of nanomedicine and nanozymes to target reactive oxygen species and selectively degrade misfolded alpha-synuclein aggregates, offering potential avenues for disease modification.