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        VOLUME 28, ISSUE 3 • SEPTEMBER 2024.  Full issue »

Research priorities on the role of α-synuclein in Parkinson's disease pathogenesis

α-Synuclein – a small protein first detected in 1988 at presynaptic terminals and nuclei of neurons – is now often considered to be synonymous with Parkinson’s disease. Indeed, α-synuclein aggregation in the form of Lewy pathology is characteristic of most forms of Parkinson’s disease, including the most common idiopathic form. Yet, despite intensive investigation into α-synuclein for more than a quarter century, the precise role of this protein in the pathogenesis and progression of Parkinson’s disease remains elusive.

To guide research efforts aimed at understanding α-synuclein’s role in Parkinson’s disease, the MDS Scientific Issues Committee (2021-2023) organized a panel of experts consisting of fundamental neuroscientists and movement disorders neurologists to discuss current scientific priorities and to identify research strategies. The MDS Scientific Issues Committee leadership carefully selected the group to represent a range of scientific expertise on the topic – from protein dynamics to electrophysiology to cell biology to neuropathology – and brought them together with leading clinician-scientists in the Parkinson’s disease field.

The following six questions were raised and addressed by the panel of experts:

  1. What are the physiologic functions of α-synuclein?
  2. What are the initial triggers of α-synuclein aggregation?
  3. What determines the distribution of α-synuclein pathology?
  4. What is the relationship between α-synuclein aggregation and neuronal dysfunction?
  5. What is the role of α-synuclein propagation in the onset and progression of Parkinson’s disease?
  6. Are neurons with α-synuclein aggregates destined to die or can they be rescued from neurodegeneration?

Discussions among the expert panel occurred during eight online meetings and an in-person meeting in Los Angeles over the course of a year. The group discussions were focused, productive, and represented a significant synergy that can be generated by bringing together fundamental scientists and clinician-scientists. The discussions resulted in an article entitled “Research Priorities on the Role of α-Synuclein in Parkinson’s Disease Pathogenesis” in Movement Disorders (DOI: 10.1002/mds.29897) with recommendations, reached by consensus, for top research priorities. These recommendations are concisely summarized in a table in the article (a simplified version is included below). The overall perspective of the panel was that developing new models and tools, as well as refining the strategy-to-target design, are critical to advance our understanding of both function and dysfunction of α-synuclein and the involvement of α-synuclein in Parkinson’s disease pathogenesis and progression.

We hope this work is not only instrumental for individual researchers by guiding their future research directions, but also influences further progress among broader Parkinson’s disease research endeavors.

Top recommended research priorities:

  • Applying physiological systems/models to characterize αSyn function at endogenous levels in native environment and non-diseased state 
  • Determining the impact of disease-associated mutations on αSyn function and fibril structure 
  • Conducting systematic analyses of αSyn regulation and the role of αSyn levels 
  • Considering cell-type specificity, cell compartment, and time requirements for studies of triggering mechanisms of αSyn aggregation 
  • Developing cell and animal models that recapitulate the different stages of αSyn aggregation 
  • Developing de novo animal models of αSyn aggregation 
  • Designing multiple target studies of primary mechanisms of αSyn folding/misfolding and aggregation
  • Systematically characterizing LP-vulnerable and LP-resistant neurons at the molecular and cellular levels 
  • Generating an unbiased, quantitative connectomic map of LP distribution 
  • Establishing standardized experimental approaches for evaluating αSyn spread using in vivo models 
  • Developing better tools to label αSyn in its various forms and cellular locations 
  • Analyzing cellular responses to LP in models and humans 
  • Developing reliable biomarkers to detect and quantify the presence and spread of pathogenic αSyn in patients across the disease spectrum (from premotor to advanced PD), and more sensitive and broadly based biomarkers of both neuronal dysfunction and neurodegeneration 
  • Prospectively studying the trajectory of people with “deleterious” SNCA SNPs who may have a more aggressive disease course 

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