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

Laura Pellegrini, David N. Hauser, Yan Li, Adamantios Mamais, Alexandra Beilina, Ravindran Kumaran, Andrea Wetzel, Jonathon Nixon-Abell, George Heaton, Iakov Rudenko, Mor Alkaslasi, Natalie Ivanina, Heather L Melrose, Mark R. Cookson, Kirsten Harvey

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3257-3271
Number of pages15
JournalHuman Molecular Genetics
Volume27
Issue number18
DOIs
StatePublished - Jan 1 2018

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Knockout Mice
Leucine
Proteomics
Proteolysis
Phosphotransferases
Mutation
Protein Biosynthesis
Kidney
Parkinson Disease
Peptide Hydrolases
IGF Type 2 Receptor
Cytoskeletal Proteins
Protein Transport
Cations
Cultured Cells
Epithelial Cells
Phenotype
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Pellegrini, L., Hauser, D. N., Li, Y., Mamais, A., Beilina, A., Kumaran, R., ... Harvey, K. (2018). Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice. Human Molecular Genetics, 27(18), 3257-3271. https://doi.org/10.1093/hmg/ddy232

Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice. / Pellegrini, Laura; Hauser, David N.; Li, Yan; Mamais, Adamantios; Beilina, Alexandra; Kumaran, Ravindran; Wetzel, Andrea; Nixon-Abell, Jonathon; Heaton, George; Rudenko, Iakov; Alkaslasi, Mor; Ivanina, Natalie; Melrose, Heather L; Cookson, Mark R.; Harvey, Kirsten.

In: Human Molecular Genetics, Vol. 27, No. 18, 01.01.2018, p. 3257-3271.

Research output: Contribution to journalArticle

Pellegrini, L, Hauser, DN, Li, Y, Mamais, A, Beilina, A, Kumaran, R, Wetzel, A, Nixon-Abell, J, Heaton, G, Rudenko, I, Alkaslasi, M, Ivanina, N, Melrose, HL, Cookson, MR & Harvey, K 2018, 'Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice', Human Molecular Genetics, vol. 27, no. 18, pp. 3257-3271. https://doi.org/10.1093/hmg/ddy232
Pellegrini, Laura ; Hauser, David N. ; Li, Yan ; Mamais, Adamantios ; Beilina, Alexandra ; Kumaran, Ravindran ; Wetzel, Andrea ; Nixon-Abell, Jonathon ; Heaton, George ; Rudenko, Iakov ; Alkaslasi, Mor ; Ivanina, Natalie ; Melrose, Heather L ; Cookson, Mark R. ; Harvey, Kirsten. / Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice. In: Human Molecular Genetics. 2018 ; Vol. 27, No. 18. pp. 3257-3271.
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