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Open AccessFeature PaperArticle

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

1
Department of Biology, University of Padova, 35131 Padova, Italy
2
Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
3
IRCCS San Camillo Hospital, 30126 Venice, Italy
4
Laboratory for Neurobiology and Gene Therapy, KU Leuven, 3000 Leuven, Belgium
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Present address: Autifony SRL, 37135, Verona, Italy.
Cells 2020, 9(11), 2344; https://doi.org/10.3390/cells9112344
Received: 14 September 2020 / Revised: 16 October 2020 / Accepted: 20 October 2020 / Published: 22 October 2020
(This article belongs to the Special Issue LRRK2-Dependent Neurodegeneration in Parkinson’s Disease)
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. View Full-Text
Keywords: LRRK2; phosphorylation; Rab10; mutant mice; striatum; cortex; midbrain; lung; kidney; age-dependent changes LRRK2; phosphorylation; Rab10; mutant mice; striatum; cortex; midbrain; lung; kidney; age-dependent changes
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Iannotta, L.; Biosa, A.; Kluss, J.H.; Tombesi, G.; Kaganovich, A.; Cogo, S.; Plotegher, N.; Civiero, L.; Lobbestael, E.; Baekelandt, V.; Cookson, M.R.; Greggio, E. Divergent Effects of G2019S and R1441C LRRK2 Mutations on LRRK2 and Rab10 Phosphorylations in Mouse Tissues. Cells 2020, 9, 2344.

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