Projects per year
Abstract
Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson’s disease (PD). G2019S, the most common amino acid substitution activates the kinase two- to threefold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics, and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2 variants mapping to different functional domains increase phosphorylation of Rabs and this strongly decreases their affinity to regulatory proteins including Rab GDP dissociation inhibitors (GDIs). Our findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD.
Original language | English |
---|---|
Article number | e12813 |
Pages (from-to) | 1-28 |
Number of pages | 28 |
Journal | eLife |
Volume | 5 |
DOIs | |
Publication status | Published - 29 Jan 2016 |
ASJC Scopus subject areas
- General Biochemistry,Genetics and Molecular Biology
- General Immunology and Microbiology
- General Medicine
- General Neuroscience
Fingerprint
Dive into the research topics of 'Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases'. Together they form a unique fingerprint.Projects
- 2 Finished
-
Role of fbx07 in Parkinson's Disease (Studentship)
Alessi, D. (Investigator)
1/10/11 → 30/09/15
Project: Research
-
Aref#d: 21286. Mass Spectrometry-Based Global Analysis of Protein Phosphorylation in Cells and Tissue Extracts with Altered PINK1 Catalytic Activity: A Novel Screen for PINK1 Substrates
Alessi, D. (Investigator) & Muqit, M. (Investigator)
1/12/09 → 30/11/12
Project: Research