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Sphingolipidoses: expanding the spectrum of α-synucleinopathies

Lookup NU author(s): Dr Daniel ErskineORCiD, Dr Agnieszka Bronowska, Professor Tiago OuteiroORCiD, Professor Johannes AttemsORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© The Author(s) 2025. Although α-synuclein pathology is typically associated with Lewy body diseases and multiple systems atrophy, increasing evidence indicates that it also occurs in a group of lysosomal storage disorders termed sphingolipidoses caused by the incomplete degradation, and subsequent accumulation, of a class of lipids termed sphingolipids. Notably, a number of genes that cause sphingolipidoses are also risk genes for Lewy body diseases, suggesting aetiological links between these distinct disorders. In the present review, we discuss the sphingolipidoses in which α-synuclein pathology has been reported: Gaucher disease, Krabbe disease, metachromatic leukodystrophy, Tay-Sachs disease and Anderson-Fabry disease, and describe the characteristic clinical and pathological features of these disorders, in addition to the evidence suggesting α-synuclein pathology occurs in these disorders. Finally, we evaluate the pathological mechanisms that underlie these rare disorders, with particular attention to how the enzymatic deficiency, substrate accumulation, or both, could contribute to the genesis of α-synuclein pathology and the implications of this for Lewy body diseases.

Publication metadata

Author(s): Erskine D, Bronowska AK, Outeiro TF, Attems J

Publication type: Review

Publication status: Published

Journal: Journal of Neural Transmission

Year: 2026

Volume: 133

Pages: 809-821

Print publication date: 01/05/2026

Online publication date: 17/04/2025

Acceptance date: 03/04/2025

ISSN (print): 0300-9564

ISSN (electronic): 1435-1463

Publisher: Springer

URL: https://doi.org/10.1007/s00702-025-02925-z

DOI: 10.1007/s00702-025-02925-z

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