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@ARTICLE{Chiang:280915,
author = {Chiang, Claire Y and Pratuseviciute, Neringa and Lin, Yu-En
and Adhikari, Ayan and Yeshaw, Wondwossen M and Flitton,
Chloe and Sherpa, Pemba L and Tonelli, Francesca and
Rektorova, Irena and Lynch, Timothy and Siuda, Joanna and
Rudzińska-Bar, Monika and Pulyk, Oleksandr and Bauer, Peter
and Beetz, Christian and Dickson, Dennis W and Ross, Owen A
and Wszolek, Zbigniew K and Fang, Zih-Hua and Klein,
Christine and Zimprich, Alexander and Alessi, Dario R and
Sammler, Esther M and Pfeffer, Suzanne R},
collaboration = {Program, Global Parkinson’s Genetics},
title = {{PPM}1{M}, an {LRRK}2-counteracting,
phospho{R}ab12-preferring phosphatase with a potential link
to {P}arkinson's disease.},
journal = {Cell reports},
volume = {44},
number = {8},
issn = {2211-1247},
address = {Maryland Heights, MO},
publisher = {Cell Press},
reportid = {DZNE-2025-00998},
pages = {116031 -},
year = {2025},
abstract = {Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a
subset of Rab GTPases that regulate receptor trafficking,
and LRRK2-activating mutations are linked to Parkinson's
disease. Rab phosphorylation is a transient event that can
be reversed by phosphatases, including protein phosphatase,
Mg2+/Mn2+ dependent 1H (PPM1H), which acts on phosphorylated
Rab 8A (phosphoRab8A) and phosphoRab10. Here, we report a
phosphatome-wide small interfering RNA (siRNA) screen that
identified PPM1M as a phosphoRab12-preferring phosphatase
that also acts on phosphoRab8A and phosphoRab10. Upon
knockout from cultured cells or mice, PPM1M displays
selectivity for phosphoRab12. As shown previously for mice
harboring LRRK2 pathway mutations, knockout of Ppm1m leads
to primary cilia loss in striatal cholinergic and
parvalbumin interneurons. We also identified a rare PPM1M
mutation in patients with Parkinson's disease that is
catalytically inactive when tested in vitro and in cells.
These findings identify PPM1M as a key player in the LRRK2
signaling pathway and provide a new therapeutic target for
the possible benefit of patients with Parkinson's disease.},
keywords = {Parkinson Disease: metabolism / Parkinson Disease: genetics
/ Parkinson Disease: pathology / Leucine-Rich Repeat
Serine-Threonine Protein Kinase-2: metabolism / Leucine-Rich
Repeat Serine-Threonine Protein Kinase-2: genetics / Animals
/ Humans / Mice / rab GTP-Binding Proteins: metabolism /
Phosphorylation / HEK293 Cells / Protein Phosphatase 2C:
metabolism / Protein Phosphatase 2C: genetics / Mutation /
Mice, Knockout / CP: Cell biology (Other) / CP: Neuroscience
(Other) / LRRK2 kinase (Other) / Parkinson’s disease
(Other) / Rab GTPase (Other) / phosphatase (Other) / primary
cilia (Other) / Leucine-Rich Repeat Serine-Threonine Protein
Kinase-2 (NLM Chemicals) / rab GTP-Binding Proteins (NLM
Chemicals) / Protein Phosphatase 2C (NLM Chemicals)},
cin = {AG Heutink},
ddc = {610},
cid = {I:(DE-2719)1210002},
pnm = {354 - Disease Prevention and Healthy Aging (POF4-354)},
pid = {G:(DE-HGF)POF4-354},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40690364},
doi = {10.1016/j.celrep.2025.116031},
url = {https://pub.dzne.de/record/280915},
}