Islam, Md Shariful, Nolte, Hendrik, Jacob, Wright, Ziegler, Anna B., Puetz, Stefanie, Grosjean, Yael ORCID: 0000-0003-0689-8344, Szczepanowska, Karolina ORCID: 0000-0003-4689-2350, Trifunovic, Aleksandra, Braun, Thomas ORCID: 0000-0002-6165-4804, Heumann, Hermann, Heumann, Rolf, Hovemann, Bernhard, Moore, Darren J. and Krueger, Marcus (2016). Human R1441C LRRK2 regulates the synaptic vesicle proteome and phosphoproteome in a Drosophila model of Parkinson's disease. Hum. Mol. Genet., 25 (24). S. 5365 - 5383. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset, autosomal dominant familial Parkinsons disease (PD) and variation at the LRRK2 locus contributes to the risk for idiopathic PD. LRRK2 can function as a protein kinase and mutations lead to increased kinase activity. To elucidate the pathophysiological mechanism of the R1441C mutation in the GTPase domain of LRRK2, we expressed human wild-type or R1441C LRRK2 in dopaminergic neurons of Drosophila and observe reduced locomotor activity, impaired survival and an age-dependent degeneration of dopaminergic neurons thereby creating a new PD-like model. To explore the function of LRRK2 variants in vivo, we performed mass spectrometry and quantified 3,616 proteins in the fly brain. We identify several differentially-expressed cytoskeletal, mitochondrial and synaptic vesicle proteins (SV), including synaptotagmin-1, syntaxin-1A and Rab3, in the brain of this LRRK2 fly model. In addition, a global phosphoproteome analysis reveals the enhanced phosphorylation of several SV proteins, including synaptojanin-1 (pThr1131) and the microtubule-associated protein futsch (pSer4106) in the brain of R1441C hLRRK2 flies. The direct phosphorylation of human synaptojanin-1 by R1441C hLRRK2 could further be confirmed by in vitro kinase assays. A protein-protein interaction screen in the fly brain confirms that LRRK2 robustly interacts with numerous SV proteins, including synaptojanin-1 and EndophilinA. Our proteomic, phosphoproteomic and interactome study in the Drosophila brain provides a systematic analyses of R1441C hLRRK2-induced pathobiological mechanisms in this model. We demonstrate for the first time that the R1441C mutation located within the LRRK2 GTPase domain induces the enhanced phosphorylation of SV proteins in the brain.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Islam, Md SharifulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nolte, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jacob, WrightUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ziegler, Anna B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Puetz, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grosjean, YaelUNSPECIFIEDorcid.org/0000-0003-0689-8344UNSPECIFIED
Szczepanowska, KarolinaUNSPECIFIEDorcid.org/0000-0003-4689-2350UNSPECIFIED
Trifunovic, AleksandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braun, ThomasUNSPECIFIEDorcid.org/0000-0002-6165-4804UNSPECIFIED
Heumann, HermannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heumann, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hovemann, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moore, Darren J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-252508
DOI: 10.1093/hmg/ddw352
Journal or Publication Title: Hum. Mol. Genet.
Volume: 25
Number: 24
Page Range: S. 5365 - 5383
Date: 2016
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
AUTOSOMAL-DOMINANT PARKINSONISM; REPEAT KINASE 2; GTP-BINDING; MICROTUBULE STABILITY; DOPAMINERGIC-NEURONS; ALPHA-SYNUCLEIN; MUTATION; PHOSPHORYLATION; GENE; DOMAINMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/25250

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