Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (9): 4247-4248.doi: 10.4103/NRR.NRR-D-25-01287

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Setting shapes the strain: Untangling alpha-synuclein heterogeneity

James A. Wiseman, Kreesan Reddy, Glenda Halliday, Birger Victor Dieriks*   

  1. Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand (Wiseman JA, Reddy K)
    Centre for Brain Research, University of Auckland, Auckland, New Zealand (Wiseman JA, Reddy K, Dieriks BV)
    Brain and Mind Centre & Faculty of Medicine and Health School of Medical Sciences, The University of Sydney, Sydney, NSW, Australia (Wiseman JA, Reddy K, Halliday G, Dieriks BV)
  • Online:2026-09-15 Published:2026-05-12
  • Contact: Birger Victor Dieriks, PhD, v.dieriks@auckland.ac.nz.
  • Supported by:
    KR is funded through an Auckland Medical Research Foundation Doctoral Scholarship. BVD is funded by a Health Research Council of New Zealand Hercus Fellowship (21/034), the School of Medical Science, University of Auckland, and Te Tītoki Mataora (3729090 & 3729858). GH is funded by the National Health and Medical Research Council of Australia (Investigator Grant 1176607). The funders had no role in study design, data collection and analysis, publication decisions, or manuscript preparation.

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Abstract: The landscape of α-synucleinopathies is both clinically and pathologically diverse, encompassing Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and several less common nonclassical syndromes, including PLA2G6-associated neurodegeneration, POLG-associated neurodegeneration, Niemann-Pick type C1, and Krabbe disease. Although each disease is defined by α-synuclein (α-Syn) aggregation, the striking diversity in onset age, anatomical distribution, and clinical course demands an explanation beyond protein misfolding alone. We contend that the key to resolving this paradox is understanding how α-Syn aggregates and their surrounding biological microenvironments co-evolve to shape disease trajectories.