<span class="paragraphSection"><div class="boxTitle">Abstract</div>Mutations in <span style="font-style:italic;">leucine-rich repeat kinase 2</span> (<span style="font-style:italic;">LRRK2</span>) cause late-onset, autosomal dominant familial Parkinson`s disease (PD) and variation at the <span style="font-style:italic;">LRRK2</span> 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 <span style="font-style:italic;">Drosophila</span> 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 <span style="font-style:italic;">in vivo</span>, 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 <span style="font-style:italic;">in vitro</span> 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 <span style="font-style:italic;">Drosophila</span> 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.</span>
from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2lIm6Hr
via IFTTT
Εγγραφή σε:
Σχόλια ανάρτησης (Atom)
Δημοφιλείς αναρτήσεις
-
from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2z8PLPw via IFTTT
-
Purpose: Loss of volume in the sub-brow fat pad with associated descent of the eyebrow is a common anatomical finding resulting in both func...
-
Publication date: October 2017 Source: International Journal of Biological Macromolecules, Volume 103 Author(s): Mingan Yu, Duqiang Liu, ...
-
Cachexia is a debilitating syndrome characterized by involuntary muscle wasting that is triggered at the late stage of many cancers. While t...
-
Abstract Endurance exercise generates CO 2 via aerobic metabolism; however, its role remains unclear. Exogenous CO 2 by transcutaneous d...
-
Publication date: Available online 5 December 2017 Source: Biochimie Author(s): Jameel Lone, Hilal Ahmad Parray, Jong Won Yun Browning of...
-
Publication date: Available online 13 April 2017 Source: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Author(s): Marcos J...
-
Publication date: October 2017 Source: Free Radical Biology and Medicine, Volume 111 from #AlexandrosSfakianakis via Alexandros G.Sfa...
-
Daily Mail Sarah was diagnosed with the cancer that killed Steve Jobs Daily Mail The symptoms Sarah Smith experienced on and off for...
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου