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Serafini 2016 Abstract Mito Xmas Meeting Innsbruck

From Bioblast
A novel role for the Parkinson’s disease gene LRRK2 as endoplasmic reticulum-mitochondria tether identified by a genome wide high content screen.

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Serafini A, Lakshminarayanan S, Giacomello, M, Scorrano L (2016)

Event: Mito Xmas Meeting 2016 Innsbruck AT

The contact sites that are formed between mitochondria and Endoplasmic Reticulum (ER) are involved in several relevant cellular processes such as lipid and Ca2+ homeostasis. Despite some of the proteins involved in the structural maintenance and regulation of the contact sites between the two organelles have been discovered, the overall molecular identity of these protein complexes is not fully understood.

Here we demonstrate that Parkinson’s disease (PD)-associated gene leucine rich repeat kinase 2 (LRRK2) is an ER-mitochondria tether, identifying a previously unknown physiological function for this protein. Based on the variations in basal and maximal FRET values of a FRET ER-Mitochondria proximity probe (FEMP) expressed in mouse embryonic fibroblasts transduced with lentiviral particles carrying shRNAs targeting the whole murine genome, we performed two replicates of a genome wide high content screening identifying 250 potential tethers. A network of genes associated to PD emerged from pathway analysis of the potential tethers, among which LRRK2 appear to be a top candidate, due to its known localization at both outer mitochondrial membrane and ER. Subcellular fractionation experiments showed that LRKK2 localized mostly in ER and mitochondria associated membranes (MAMs). As expected for a tether, levels of ER-mitochondria juxtapposition were decreased in LRRK2-/- cells. ER-mitochondria proximity was fully rescued by reintroduction in LRRK2-/- cells of wt protein, but not of the familial PD-associated mutants. In conclusion, LRRK2 is involved in tethering between ER and mitochondria and its PD associated mutations impair interorganellar juxtaposition and communication.


Labels: Pathology: Parkinson's 

Organism: Mouse  Tissue;cell: Fibroblast 




Event: Poster 


Affiliations

Serafini A(1), Lakshminarayanan S(1,2), Giacomello, M(1,3), Scorrano L(1,2)
  1. Dept Biology, Univ Padova and Dulbecco-Telethon Inst,
  2. Dulbecco-Telethon Inst, Venetian Inst Molecular Medicine, Padova, Italy
  3. Fondazione Ospedale San Camillo, IRCCS, Lido di Venezia, Italy