Citations 2
PPM1M, a LRRK2-counteracting, phosphoRab12-preferring phosphatase with potential link to Parkinson’s disease
Chiang, Claire Y , Pratuseviciute, Neringa , Lin, Yu‐En , Adhikari, Ayan , Yeshaw, Wondwossen M , Flitton, Chloe , Sherpa, Pemba , Tonelli, Francesca , Lynch, Timothy , Siuda, Joanna , Pulyk, O. R. , Sherpa, Pemba L , Rektorova, Irena , Lynch, Timothy , Siuda, Joanna S. , Pulyk, Oleksandr , Bauer, Peter , Beetz, Christian , Dickson, Dennis W , Ross, Owen A , Wszolek, Z.K. , Klein, Christine , Zimprich, Alexander , Alessi, Dario R , Sammler, Esther M , Pfeffer, Suzanne R , Tonelli, Francesca , Rektorová, Irena , Rudzińska, Monika , Dickson, Dennis W. , Ross, Owen A. , Wszołek, Zbigniew K. , Klein, Christine , Zimprich, Alexander , Alessi, Dario R. , Sammler, Esther
No container title available | March 21, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking; activating mutations in LRRK2 are linked to Parkinson’s disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including PPM1H, that acts on phosphoRab8A and phosphoRab10. Here we report a phosphatome-wide siRNA screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10. Upon knockout from 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 interneurons. We have 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. Teaser Parkinson’s linked Rab phosphorylation is reversed by PPM1M; the inactive D440N variant is implicated in rare patient cases.
Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain
Bagnoli, Enrico , Lin, Yu‐En , Jaimon, Ebsy , Antico, Odetta , Themistokleous, Christos , Nikoloff, Jonas , Squires, Samuel, Morella, Ilaria , Fiesel, Fabienne C. , Tonelli, Francesca , Lis, Paweł , Brambilla, Riccardo , Alessi, Dario R. , Jaimon, Ebsy , Antico, Odetta , Nikoloff, Jonas M , Morella, Ilaria , Watzlawik, Jens O , Fiesel, Fabienne C , Springer, Wolfdieter , Tonelli, Francesca , Lis, Pawel , Alessi, Dario R , Pfeffer, Suzanne R , Muqit, Miratul Mk , Burel, Sophie , Squires, Samuel, Watzlawik, Jens O. , Springer, Wolfdieter , Brooks, Simon P. , Dunnett, Stephen B. , Muqit, Miratul M. K.
Proceedings of the National Academy of Sciences | January 28, 2025 | Volume: 122 | Issue: 5 | Pages: No page available
Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1) are associated with familial Parkinson’s disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2-mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1-mediated Rab and Ub phosphorylation. In addition, we observe that a pool of the Rab-specific, protein phosphatase family member 1H phosphatase, is transcriptionally up-regulated and recruited to damaged mitochondria, independent of PINK1 or LRRK2 activity. Parallel signaling of LRRK2 and PINK1 pathways is supported by assessment of motor behavioral studies that show no evidence of genetic interaction in crossed mouse lines. Previously we showed loss of cilia in LRRK2 R1441C mice and herein we show that PINK1 KO mice exhibit a ciliogenesis defect in striatal cholinergic interneurons and astrocytes that interferes with Hedgehog induction of glial derived-neurotrophic factor transcription. This is not exacerbated in double-mutant LRRK2 and PINK1 mice. Overall, our analysis indicates that LRRK2 activation and/or loss of PINK1 function along parallel pathways to impair ciliogenesis, suggesting a convergent mechanism toward PD. Our data suggest that reversal of defects downstream of ciliogenesis offers a common therapeutic strategy for LRRK2 or PINK1 PD patients, whereas LRRK2 inhibitors that are currently in clinical trials are unlikely to benefit PINK1 PD patients.