Rising Stars: Molecular Mechanisms and Chemical Interventions of α-Synuclein Amyloid Aggregation in Parkinson’s Disease
Bibliographic record
Abstract
• Parkinson’s disease (PD) is a major neurodegenerative disorder characterized by pathological aggregation of α-synuclein (α-syn). • This Perspective highlights our decade-long efforts to elucidate the molecular mechanisms of α-synuclein aggregation in Parkinson’s disease. • We reveal atomic-resolution fibril polymorphs shaped by familial mutations and post-translational modifications, define the structural determinants of fibril–ligand interactions guiding the design of imaging tracers and therapeutic modulators, and uncover receptor-mediated recognition and cell-to-cell transmission pathways that drive disease propagation. • Together, these insights establish a molecular foundation for precision diagnostics and targeted interventions in Parkinson’s disease and related synucleinopathies. Parkinson’s disease (PD) is a prevalent neurodegenerative disorder characterized by progressive neuronal loss and pathological aggregation of α-synuclein (α-syn) into amyloid fibrils, which propagate between cells and drive disease progression. Over the past decade, our laboratory has implemented an integrated strategy—combining high-resolution structural biology, molecular biophysics, biochemical and cellular analyses, chemical biology approaches, and in vivo disease models—to elucidate the molecular basis of α-syn pathology. We first determined atomic-resolution structures of full-length α-syn fibrils, revealing diverse polymorphs shaped by familial mutations and post-translational modifications, and linking conformational heterogeneity to phenotypic and pathological diversity. We further elucidated the structural basis underlying the interaction between amyloid fibril and chemical ligands, enabling the rational development of imaging probes and therapeutic modulators. In parallel, we found that the conserved acidic C-terminal region of α-syn fibrils acts as a central interface for driving pathogenic engagement with multiple receptors for neural propagation and inflammation induction, while also binding the autophagy adaptor LC3B to disrupt p62-mediated selective autophagy. Targeting this interface with small molecule inhibitors alleviates α-syn–induced toxicity in cellular models. Together, these findings provide an integrated molecular roadmap for understanding α-syn pathology and advancing precision diagnostics and targeted interventions in PD and related synucleinopathies.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".