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More than meets the eye in Parkinson’s disease and other synucleinopathies: from proteinopathy to lipidopathy

Lookup NU author(s): Professor Tiago OuteiroORCiD



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


© 2023, The Author(s). The accumulation of proteinaceous inclusions in the brain is a common feature among neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease (PD), and dementia with Lewy bodies (DLB). The main neuropathological hallmark of PD and DLB are inclusions, known as Lewy bodies (LBs), enriched not only in α-synuclein (aSyn), but also in lipid species, organelles, membranes, and even nucleic acids. Furthermore, several genetic risk factors for PD are mutations in genes involved in lipid metabolism, such as GBA1, VSP35, or PINK1. Thus, it is not surprising that mechanisms that have been implicated in PD, such as inflammation, altered intracellular and vesicular trafficking, mitochondrial dysfunction, and alterations in the protein degradation systems, may be also directly or indirectly connected through lipid homeostasis. In this review, we highlight and discuss the recent evidence that suggests lipid biology as important drivers of PD, and which require renovated attention by neuropathologists. Particularly, we address the implication of lipids in aSyn accumulation and in the spreading of aSyn pathology, in mitochondrial dysfunction, and in ER stress. Together, this suggests we should broaden the view of PD not only as a proteinopathy but also as a lipidopathy.

Publication metadata

Author(s): Flores-Leon M, Outeiro TF

Publication type: Review

Publication status: Published

Journal: Acta Neuropathologica

Year: 2023

Volume: 146

Pages: 369-385

Online publication date: 08/07/2023

Acceptance date: 14/06/2023

ISSN (print): 0001-6322

ISSN (electronic): 1432-0533

Publisher: Springer Science and Business Media Deutschland GmbH


DOI: 10.1007/s00401-023-02601-0