PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins

Berndsen, Kerryn; Lis, Paweł; Yeshaw, Wondwossen M; Wawro, Paulina S.; Nirujogi, Raja Sekhar; Wightman, Melanie; Macartney, Thomas; Dorward, Mark; Knebel, Axel; Tonelli, Francesca; Pfeffer, Suzanne R.; Alessi, Dario R.

doi:10.1101/711176

Cited by 27 publications

(58 citation statements)

References 70 publications

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“…We suggest that this enzyme may counteract the hyperactive kinase by as yet undiscovered feedback mechanisms. Interestingly, knockdown of ALPI has been shown to decrease both LRRK2 levels and activity in cells [76]. We also found several lysosomal proteins including α-and β-subunit of βhexosaminidase A (HEXA and HEXB), GM2A and GCase, whose genes are associated with LSDs, to be upregulated in LRRK2 G2019S carriers in both cohorts.…”

Section: Discussionsupporting

confidence: 50%

Urinary proteome profiling for stratifying patients with familial Parkinson’s disease

Winter

Karayel

Strauss

et al. 2020

Preprint

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The prevalence of Parkinson's disease (PD) is increasing but the development of novel treatment strategies and therapeutics altering the course of the disease would benefit from specific, sensitive and non-invasive biomarkers to detect PD early. Here, we describe a scalable and sensitive mass spectrometry (MS)-based proteomic workflow for urinary proteome profiling. Our workflow enabled the reproducible quantification of more than 2,000 proteins in more than 200 urine samples using minimal volumes from two independent patient cohorts. The urinary proteome was significantly different between PD patients and healthy controls, as well as between LRRK2 G2019S carriers and non-carriers in both cohorts. Interestingly, our data revealed lysosomal dysregulation in individuals with the LRRK2 G2019S mutation. When combined with machine learning, the urinary proteome data alone was sufficient to classify mutation status and disease manifestation in mutation carriers remarkably well, identifying VGF, ENPEP and other PD-associated proteins as the most discriminating features. Taken together, our results validate urinary proteomics as a valuable strategy for biomarker discovery and patient stratification in PD.

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Section: Discussionsupporting

confidence: 50%

Urinary proteome profiling for stratifying patients with familial Parkinson’s disease

Winter

Karayel

Strauss

et al. 2020

Preprint

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“…Second, R1441C but not G2019S results in increased phospho-Rab10, at least in kidneys and lungs where detection of phospho-Rab10 was possible ( Figure 6 b). The lack of phospho-Rab10 detection in the brain may be explained by the high expression levels in this tissue of PPM1H, a phosphatase selectively dephosphorylating Rab GTPases [ 11 ]. Furthermore, the R1441C mutation dramatically reduces Ser935 phosphorylation ( Figure 6 b), in line with cellular studies [ 5 , 6 ], instead the phosphorylation tone of Ser935 in GSKI is in between WT and RCKI ( Figure 6 b).…”

Section: Discussionmentioning

confidence: 99%

“…As predicted, Ser1292-LRRK2 and Thr73-Rab10 are hyperphosphorylated in the presence of gain of function LRRK2 mutants in cells and mouse and human peripheral tissues [ 3 , 7 , 8 , 9 ], as well as in the substantia nigra (SN) dopaminergic neurons of postmortem brain tissue from idiopathic PD patients [ 10 ]. Despite being well-established in cells, Rab10 phosphorylation in the brain has proven difficult to detect, possibly due to the high levels of PPM1H, a phosphatase selectively dephosphorylating Rab GTPases [ 11 ], or to a lower basal activity of LRRK2 in neuronal cells compared to peripheral tissues.…”

Section: Introductionmentioning

confidence: 99%

Divergent Effects of G2019S and R1441C LRRK2 Mutations on LRRK2 and Rab10 Phosphorylations in Mouse Tissues

Iannotta

Biosa

Kluss

et al. 2020

Cells

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Mutations in LRRK2 cause familial Parkinson’s disease and common variants increase disease risk. LRRK2 kinase activity and cellular localization are tightly regulated by phosphorylation of key residues, primarily Ser1292 and Ser935, which impacts downstream phosphorylation of its substrates, among which Rab10. A comprehensive characterization of LRRK2 activity and phosphorylation in brain as a function of age and mutations is missing. Here, we monitored Ser935 and Ser1292 phosphorylation in midbrain, striatum, and cortex of 1, 6, and 12 months-old mice carrying G2019S and R1441C mutations or murine bacterial artificial chromosome (BAC)-Lrrk2-G2019S. We observed that G2019S and, at a greater extent, R1441C brains display decreased phospho-Ser935, while Ser1292 autophosphorylation increased in G2019S but not in R1441C brain, lung, and kidney compared to wild-type. Further, Rab10 phosphorylation, is elevated in R1441C carrying mice, indicating that the effect of LRRK2 mutations on substrate phosphorylation is not generalizable. In BAC-Lrrk2-G2019S striatum and midbrain, Rab10 phosphorylation, but not Ser1292 autophosphorylation, decreases at 12-months, pointing to autophosphorylation and substrate phosphorylation as uncoupled events. Taken together, our study provides novel evidence that LRRK2 phosphorylation in mouse brain is differentially impacted by mutations, brain area, and age, with important implications as diagnostic markers of disease progression and stratification.

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“…In contrast, cellular phosphorylation of Rab GTPases is more subtle in terms of chemistry, and may be reversible through the action of protein phosphatases. Recently, PPM1H phosphatase has been shown to counter the LRRK2 signaling cascade through dephosphorylation of pRab8a and pRab10 46 . In summary, many of the phospho‐Rabs in Table 1 have unknown mechanistic implications, poorly defined roles in trafficking, and the specific kinase remains a mystery.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Rab GTPases in the regulation of membrane trafficking

Waschbüsch

Khan

2020

Traffic

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Rab GTPases are master regulators of membrane trafficking in eukaryotic cells. Phosphorylation of Rab GTPases was characterized in the 1990s and there have been intermittent reports of its relevance to Rab functions. Phosphorylation as a regulatory mechanism has gained prominence through the identification of Rabs as physiological substrates of leucine‐rich repeat kinase 2 (LRRK2). LRRK2 is a Ser/Thr kinase that is associated with inherited and sporadic forms of Parkinson disease. In recent years, numerous kinases and their associated signaling pathways have been identified that lead to phosphorylation of Rabs. These emerging studies suggest that serine/threonine and tyrosine phosphorylation of Rabs may be a widespread and under‐appreciated mechanism for controlling their membrane trafficking functions. Here we survey current knowledge of Rab phosphorylation and discuss models for how this post‐translational mechanism exerts control of membrane trafficking.

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PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins

Cited by 27 publications

References 70 publications

Urinary proteome profiling for stratifying patients with familial Parkinson’s disease

Urinary proteome profiling for stratifying patients with familial Parkinson’s disease

Divergent Effects of G2019S and R1441C LRRK2 Mutations on LRRK2 and Rab10 Phosphorylations in Mouse Tissues

Phosphorylation of Rab GTPases in the regulation of membrane trafficking

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