α-Synuclein Propagation, Staging, and Disease Progression in Parkinson’s Disease and Related Synucleinopathies

Misfolding and aggregation of α-synuclein are central pathological features of Parkinson’s disease and related synucleinopathies. While these proteinopathies have been intensively studied, effective disease-modifying therapies remain elusive. Recent work suggests that α-synuclein can adopt different forms (including conformers or putative strains), and that some synucleinopathies, especially rapidly progressing types, may involve α-synuclein species with higher aggregation, seeding, and propagation potential. These findings continue to shape debates on the molecular basis of disease progression and the clinical significance of biomarkers for diagnosis, prognosis, and staging. However, important gaps remain in linking molecular events to clinical outcomes, and in understanding how aging-related factors influence the initiation, spread, and clearance of
pathogenic α-synuclein. More direct links to clinically meaningful outcomes are needed to support translation and inform targeted therapeutic strategies.

In plain terms, this Research Topic centers on how α-synuclein pathology may propagate and be staged across brain regions throughout the disease course, and how this relates to clinical features, biomarkers, and therapeutic directions. This Research Topic aims to advance the field by bringing together contributions that clarify how α-synuclein aggregates form, spread, and vary across Parkinson’s disease and related synucleinopathies, with particular attention to the aging related disease continuum. The objective is to stimulate research that connects mechanisms to patient-relevant outcomes, including progression and staging, and that informs therapeutic approaches such as modulation of aggregation, propagation, and cellular clearance pathways (including lysosomal function and autophagy). Key questions include: What shapes the regional and temporal patterns of α-synuclein pathology? How might different α-synuclein forms contribute to clinical heterogeneity? And how can these insights guide biomarker and therapeutic development?

This Research Topic welcomes studies that bridge mechanistic and translational domains, focusing on α-synuclein pathology within Parkinson’s disease and related synucleinopathies. Submissions are most suitable when they clearly relate to disease progression, staging, biomarkers, and/or therapeutic implications, including:

- Mechanistic laboratory studies (in vitro, ex vivo, and in vivo) with clear clinical relevance, including biomarker, neuropathological, or therapeutic implications

- Clinical and translational biomarker research (for example CSF, blood, imaging, and seeding amplification assays)

- Neuropathology and clinicopathological studies that refine staging systems or clinico pathological correlations

- Reviews (systematic, scoping, or narrative) synthesizing evidence for pathogenesis, biomarkers, or therapies

- Methods and technology papers that present or validate a tool or approach that helps study α-synuclein pathology and disease progression, ideally with robust clinically relevant validation (for example well-characterized patient cohorts, clinically annotated samples, clear performance metrics, and links to meaningful outcomes)

Topic Editor Dr. Coughlin receives research funding from the Michael J. Fox Foundation and in-kind support from Amprion and CND. Topic Editor Dr. Nakamura declares no competing interests.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: α-synuclein, aggregation, intercellular propagation, autophagy, disease-modifying therapy, Parkinson’s disease, synucleinopathies, biomarkers

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.