Evidence map›Paper›PMID 42166327›Full record

ArticleCell reports2026

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

Michel Fricke, Anna Mechel, Lennart Evers, Björn Twellsieck, Jessica M Grein, Maria-Sol Cima-Omori, Mohammed Al-Azzani, Tiago F Outeiro, Markus Zweckstetter, Erika L F Holzbaur and 1 more

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In one paragraph

Article in Cell reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Michel FrickeUniversity Medical Center Goettingen, Department of Neurology, 37077 Goettingen, Germany.
Anna MechelUniversity Medical Center Goettingen, Department of Neurology, 37077 Goettingen, Germany.
Lennart EversUniversity Medical Center Goettingen, Department of Neurology, 37077 Goettingen, Germany.
Björn TwellsieckUniversity Medical Center Goettingen, Department of Neurology, 37077 Goettingen, Germany.
Jessica M GreinUniversity Medical Center Goettingen, Department of Neurology, 37077 Goettingen, Germany.
Maria-Sol Cima-OmoriGerman Center for Neurodegenerative Diseases (DZNE), 37075 Goettingen, Germany.
Mohammed Al-AzzaniUniversity Medical Center Goettingen, Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, 37073 Goettingen, Germany.
Tiago F OuteiroGerman Center for Neurodegenerative Diseases (DZNE), 37075 Goettingen, Germany; University Medical Center Goettingen, Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, 37073 Goettingen, Germany; Faculdade de Medicina e Ciências Biomédicas, Algarve Biomedical Center Research Institute (ABC-Ri), Universidade do Algarve, 8005-139 Faro, Portugal; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.
Markus ZweckstetterGerman Center for Neurodegenerative Diseases (DZNE), 37075 Goettingen, Germany; Department for NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, 37077 Goettingen, Germany.
Erika L F HolzbaurDepartment of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
C Alexander BoeckerUniversity Medical Center Goettingen, Department of Neurology, 37077 Goettingen, Germany. Electronic address: alexander.boecker@med.uni-goettingen.de.

Funding

Mechanistic analysis of axonal transport defects in motor neuron degenerative disR01NS060698 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI HOLZBAUR, ERIKA L · 2008 to 2025
$3.8M
NINDS NIH HHS R01 NS060698
6 · The paper itself

Abstract

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.

Indexed as

alpha-SynucleinAutophagyAxonsLeucine-Rich Repeat Serine-Threonine Protein Kinase-2Protein AggregatesProtein Phosphatase 2Crab GTP-Binding ProteinsAnimalsAutophagosomesHumansMiceNeuronsPhosphorylationalpha-SynucleinLeucine-Rich Repeat Serine-Threonine Protein Kinase-2Protein AggregatesProtein Phosphatase 2Crab GTP-Binding Proteinsalpha-synucleinautophagyaxonal transportCP: Cell biologyCP: NeuroscienceLRRK2PPM1HRAB GTPases

Identifiers

PMID42166327
PMCPMC13196427

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.