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Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation

Lookup NU author(s): Professor Tiago OuteiroORCiD

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

Abstract

© 2026 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/. Parkinson disease (PD)-associated mutations in the LRRK2 gene hyperactivate LRRK2 kinase activity, leading to increased phosphorylation of a subset of RAB GTPases, which are master regulators of intracellular trafficking. In neurons, processive retrograde transport of autophagosomes is essential for autophagosome maturation and effective degradation of autophagosomal cargo in the axon. Here, we show that knockout of the LRRK2-counteracting RAB phosphatase PPM1H causes a gene-dose-dependent disruption of the axonal transport of autophagosomes, leading to impaired degradation of axonal alpha-synuclein (aSyn), a key protein in PD pathophysiology. Defective autophagosome transport and impaired aSyn degradation correlate with increased aSyn aggregation in primary PPM1H knockout neurons exposed to preformed fibrils of aSyn, an effect that is dependent on LRRK2 kinase activity. These findings mechanistically link LRRK2-mediated RAB hyperphosphorylation to defective autophagosomal degradation and enhanced aggregation of aSyn, positioning the LRRK2-RAB axis as a key driver of PD pathophysiology.

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Author(s): Fricke M, Mechel A, Evers L, Twellsieck B, Grein JM, Cima-Omori M-S, Al-Azzani M, Outeiro TF, Zweckstetter M, Holzbaur ELF, Boecker CA

Publication type: Article

Publication status: Published

Journal: Cell Reports

Year: 2026

Volume: 45

Issue: 6

Print publication date: 23/06/2026

Online publication date: 21/05/2026

Acceptance date: 17/04/2026

Date deposited: 01/06/2026

ISSN (print): 2639-1856

ISSN (electronic): 2211-1247

Publisher: Elsevier BV

URL: https://doi.org/10.1016/j.celrep.2026.117364

DOI: 10.1016/j.celrep.2026.117364

Data Access Statement: All data reported in this paper will be shared by the lead contact upon request. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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