TL;DR
This review focuses on translational insights linking α-syn pathology to dysregulated stress-response and protein quality-control pathways, intending to identify potential targets for disease-modifying intervention.
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized pathologically by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies, which predominantly consist of misfolded α-synuclein (α-Syn) aggregates. Recent advances have highlighted the critical role of the interplay between α-Syn and lysosomal function, termed the α-Syn-lysosome axis, as a central mechanism underlying PD pathogenesis. This review systematically summarizes the molecular mechanisms driving α-Syn aggregation and the lysosomal dysfunction contributing to impaired autophagy-lysosome pathway (ALP) activity. We further discuss emerging therapeutic strategies targeting this axis to restore lysosomal function and mitigate α-Syn toxicity. By integrating the latest findings from molecular biology, cell biology, and preclinical studies, this article aims to elucidate the complex regulatory network of the α-Syn-lysosome axis and provide a theoretical foundation for the development of novel therapeutic interventions for PD.
Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the accumulation and propagation of α-synuclein (α-syn). Although α-syn aggregation is considered central to PD pathogenesis, increasing evidence suggests that α-syn abundance may be as important as its conformational state. Genetic studies have demonstrated an SNCA dosage effect, with gene duplication and triplication associated with progressively more severe familial PD phenotypes. Complementary evidence indicates that dysfunction of protein clearance pathways, particularly the autophagy–lysosome system, promotes intracellular α-syn accumulation and increases its neurotoxic potential. In this review, we propose α-syn multiplication as an integrative framework for interpreting PD pathogenesis. This concept extends beyond SNCA copy-number variation to encompass processes that increase the effective α-syn burden within neurons or across neural networks, including increased gene expression, impaired degradation, disrupted proteostasis, and pathological propagation. Methods We summarize α-syn structural dynamics and the concentration-dependent distribution of monomeric, oligomeric, and fibrillar species. We then review evidence from SNCA gene-dosage studies and examine the role of the autophagy–lysosome pathway in regulating α-syn homeostasis, with particular emphasis on recent experimental findings demonstrating that autophagy deficiency exacerbates α-syn accumulation and neurodegeneration in human α-syn bacterial artificial chromosome transgenic mice. Results Collectively, the available genetic, biochemical, and experimental evidence supports a model in which the balance between α-syn production and clearance influences disease progression alongside protein misfolding. The interaction between increased protein burden and impaired clearance capacity provides a unifying mechanism linking familial and sporadic forms of PD. Discussion We propose that α-syn multiplication offers an integrative framework for understanding PD pathogenesis, provides a quantitative perspective on disease heterogeneity, and highlights therapeutic opportunities aimed at reducing α-syn burden and restoring proteostatic balance.
This integrated framework reframes PD as a disorder of impaired cellular maintenance rather than solely a consequence of late-stage degenerative processes, and provides a translational shift from mechanism-based biomarkers to early detection of mitochondrial failure and supports therapeutic strategies aimed at restoring mitochondrial function and resilience.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the pathological misfolding and aggregation of α-synuclein (α-syn), which leads to dopaminergic neuronal loss and multisystem dysfunction. Conventional clinical diagnosis is often delayed until after substantial neuronal degeneration has occurred. Recent advances in α-syn seed amplification assays (α-syn SAAs), including real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), have revolutionized PD biomarker research. These assays exploit the prion-like seeding and propagation properties of pathological α-syn to amplify trace aggregates in biological samples with exceptional sensitivity and specificity. Here, we summarize the mechanistic principles and biophysical underpinnings of α-syn SAAs, compare their diagnostic performance across biospecimens such as cerebrospinal fluid, skin, blood, and saliva, and evaluate their potential for differential diagnosis among synucleinopathies. We further discuss the integration of SAAs with other biomarkers including α-syn oligomer ELISAs, neurofilament light chain assays, and dopaminergic PET/SPECT imaging. Emerging developments, such as same-day RT-QuIC, quantitative kinetic readouts, and peripheral blood-based assays, are accelerating clinical translation. Despite challenges in assay standardization, strain discrimination, and regulatory validation, α-syn SAAs hold transformative potential for early diagnosis, patient stratification, and monitoring of therapeutic efficacy in PD. Their convergence with artificial intelligence, organoid modeling, and multimodal biomarker frameworks promises to redefine precision medicine in PD and other synucleinopathies.
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