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Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders

Lookup NU author(s): Dr Daniel ErskineORCiD, Dr David KossORCiD, Dr Viktor Korolchuk, Professor Tiago OuteiroORCiD, Professor Johannes Attems, Professor Ian McKeith



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


© 2021, The Author(s). Accumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.

Publication metadata

Author(s): Erskine D, Koss D, Korolchuk VI, Outeiro TF, Attems J, McKeith I

Publication type: Review

Publication status: Published

Journal: Acta Neuropathologica

Year: 2021

Volume: 141

Pages: 511-526

Print publication date: 01/04/2021

Online publication date: 30/01/2021

Acceptance date: 15/01/2021

ISSN (print): 0001-6322

ISSN (electronic): 1432-0533

Publisher: Springer Science and Business Media Deutschland GmbH


DOI: 10.1007/s00401-021-02266-7