Multi-omics comparative analyses of synucleinopathy models reveal distinct drug targets and relevance for drug development

Translational Insights into α-Synuclein Aggregation and Proteostasis Dysfunction in Parkinson’s Disease

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.

Cellular prion protein levels modulate nigrostriatal vulnerability to α-synuclein oligomers in Parkinson’s disease

α-Synuclein oligomer (αSynO)-mediated neurodegeneration is a hallmark of Parkinson’s disease (PD) pathogenesis, yet the molecular mechanisms mediating this toxicity remain elusive. In this study, we investigated the cellular prion protein (PrP C ) as a key modulator of αSynO-induced neurodegeneration using an integrative translational approach combining human transcriptomic analysis with in vivo bidirectional genetic modulation in mice. Bioinformatics analysis of postmortem substantia nigra samples revealed that the PRNP gene is significantly upregulated in idiopathic PD patients, with its co-expression network enriched for plasma membrane raft organization and synaptic vesicle dynamics. Single-cell RNA-seq confirmed that PRNP expression is predominantly neuronal and expressed at low levels in microglia. To validate these findings, we performed intrastriatal αSynO injections in PrP C -knockout (PrnpKO), PrP C -overexpressing (Tg20), and wild-type (WT) mice. Immunohistochemical analysis at 30 days post-injection revealed that dopaminergic vulnerability was determined by PrP C expression levels. Tg20 mice exhibited reduced tyrosine hydroxylase immunoreactivity in the caudate-putamen, while PrnpKO mice were protected. Behavioral assessment showed that PrP C levels modulate baseline motor performance, with Tg20-αSynO mice consistently displaying the most severe motor impairment. RT-qPCR analysis of striatal transcripts/mRNA levels revealed genotype-specific neuroinflammatory responses to αSynO. WT mice mounted a selective anti-inflammatory Arginase 1 response, PrnpKO mice partially resolved their basal pro-inflammatory profile, whereas Tg20 mice exhibited pro-inflammatory exacerbation with significant upregulation of Tnfα and Il1β . Together, these findings identify PrP C expression levels as an important modulator of nigrostriatal vulnerability and neuroinflammatory phenotype in response to αSynO, supporting the hypothesis that PrP C contributes to αSynO-mediated pathogenic mechanisms.

α-Synuclein burden amplification in Parkinson’s disease: a unified genetic, molecular, and cellular framework

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.

Atorvastatin Shows Limited Disease-Modifying Effects in an A53T α-Synuclein Mouse Model of Parkinson’s Disease

Neuroprotective effects of statins in Parkinson’s disease (PD) remain uncertain, and their activity in genetic α-synuclein (αSyn) disease models has been insufficiently characterized. We evaluated atorvastatin (ATO) in a mouse model with nigral overexpression of human A53T-mutant αSyn. Mice received ATO by oral gavage at 10 mg/kg/day for 5 weeks and were assessed using behavioral testing, neuropathological assessment, brain transcriptomics, and molecular docking. ATO inhibited cholesterol biosynthesis-related transcriptional programs and broadly remodeled lipid metabolism-associated networks, but did not lead to functional or histopathological benefit. ATO did not ameliorate motor deficits, restore dopaminergic markers, or reduce αSyn protein levels or pSer129-αSyn immunoreactivity. Transcriptomic analysis further showed that ATO failed to reverse the core disease-associated signature induced by A53T αSyn overexpression and instead increased SNCA mRNA. Targeted RNA-seq and western blot analyses showed no parallel increase in Prkn, Gba1, or Lamp2 transcript abundance or in PARKIN, GBA1, or LAMP2A protein expression. Molecular docking, used here as an exploratory structural comparison, suggested a relatively weak predicted interaction between ATO and αSyn when compared with several other statins and provided supportive context for the lack of efficacy. Overall, our findings indicate limited efficacy of ATO in this αSyn-driven setting and support further comparative evaluation of individual statins across complementary PD models.

Integrated In Vivo and In Vitro Analysis of Alpha-Synuclein Aggregation and Neuroinflammatory Amplification in a Composite Parkinson’s Disease Model

Research progress on the α-synuclein-lysosome axis in Parkinson’s disease: molecular mechanisms of protein aggregation, autophagy dysfunction, and therapeutic targeting

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.