Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice.

Autor:	Pellegrini L; Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA.; Department of Pharmacology, UCL School of Pharmacy, University College London, London, UK., Hauser DN; Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA., Li Y; Mass-spetrometry Facility, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD, USA., Mamais A; Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA., Beilina A; Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA., Kumaran R; Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA., Wetzel A; Department of Pharmacology, UCL School of Pharmacy, University College London, London, UK., Nixon-Abell J; Department of Pharmacology, UCL School of Pharmacy, University College London, London, UK.; Neurogenetics Branch, National Institute of Neurological Disorders and Stroke - National Institutes of Health, Bethesda, MD, USA., Heaton G; Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA.; Department of Pharmacology, UCL School of Pharmacy, University College London, London, UK., Rudenko I; Department of Neurology, SUNY at Stony Brook, Health Science Center, Stony Brook, NY, USA., Alkaslasi M; Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA., Ivanina N; Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA., Melrose HL; Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA., Cookson MR; Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA., Harvey K; Department of Pharmacology, UCL School of Pharmacy, University College London, London, UK.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2018 Sep 15; Vol. 27 (18), pp. 3257-3271.
DOI:	10.1093/hmg/ddy232
Abstrakt:	Mutations in leucine-rich repeat kinase 2 (LRRK2) segregate with familial Parkinson's disease (PD) and genetic variation around LRRK2 contributes to risk of sporadic disease. Although knockout (KO) of Lrrk2 or knock-in of pathogenic mutations into the mouse germline does not result in a PD phenotype, several defects have been reported in the kidneys of Lrrk2 KO mice. To understand LRRK2 function in vivo, we used an unbiased approach to determine which protein pathways are affected in LRRK2 KO kidneys. We nominated changes in cytoskeletal-associated proteins, lysosomal proteases, proteins involved in vesicular trafficking and in control of protein translation. Changes were not seen in mice expressing the pathogenic G2019S LRRK2 mutation. Using cultured epithelial kidney cells, we replicated the accumulation of lysosomal proteases and demonstrated changes in subcellular distribution of the cation-independent mannose-6-phosphate receptor. These results show that loss of LRRK2 leads to co-ordinated responses in protein translation and trafficking and argue against a dominant negative role for the G2019S mutation.
Databáze:	MEDLINE
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