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Serafini, Annalisa (2017) A FRET-based genome wide high content screen identifies a novel role for the Parkinson's disease gene LRRK2 as modulator of endoplasmic reticulum-mitochondria tethering. [Ph.D. thesis]

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Abstract (english)

Inter-organelle communication is a key feature of eukaryotic cells and has been found to be fundamental in many different cellular processes. One of the best characterized interorganelle cross talk due to membrane contact sites is that between Endoplasmic Reticulum (ER) and mitochondria. Also referred to as mitochondria associated ER-membranes (MAMs) or Mitochondria-ER contact sites (MERCs), their existence was discovered 50 years ago through electron microscopic studies, but their functional significance started to emerge only in late 90s when the role of MERCs in calcium exchange from ER to mitochondria was demonstrated. Despite the importance of these contacts sites in physiology and pathology, only few proteins have so far been identifed involved in the structural maintenace of the distance between the two organelles in mammals. Mitofusin 2 (MFN2) was the first structural tether to be identified. MFN2 has been found on both OMM and ER cytosolic face and is able to form homo and heterotypic interactions with MFN1, thus tethering the two organelles. As residual juxtaposition between the two organelles is still observed in Mfn2-/- cells, additional tethering proteins have to exist. To identify them, we set out to perform two replicates of a genome wide screening in mouse embryonic fibroblasts (MEFs). In order to perform the genome wide screening, we capitalized on the FRET based biosensor, where CFP fused with FRB domain and YFP fused with FKBP domain were targeted to ER (by a Sac 1 signaling sequence) and mitochondria (by an Akap signaling sequence) respectively (Csordas et al., 2010). We modified this probe by introducing between the cDNAs of the two fluorescent proteins a self-cleaving Tav2A peptide in order to have a single mRNA construct that allows the expression of equimolar level of the proteins. FKBP and FRB binding domain are able to heterodymerize upon addition of rapamycin, thus allowing the measurement not only of the basal level of juxtaposition between the two organelles, but also of the maximum level of contacts that can occur in a cell. We called this new construct FRET ER-mitochondria probe (FEMP). FEMP unique features allow us to discriminate between proteins whose role is keeping the two organelles closer, termed as "tethers", and proteins that keep the two organelles apart, defined as "spacers".
We analyzed raw images from the screen and calculated two indexes, namely basal and maximum MERC index, mirroring the level of contacts observed at any given timepoint and the maximum possible level of contacts respectively. Following automated image analysis and statistical analysis performed on ~10,000 genes, after candidate selection we identified 205 genes as ER-mitochondria tethers (i.e., genes that once ablated increase the distance between the two organelles) and 59 genes as spacers (i.e., genes that once ablated decrease the distance between the two organelles) affecting both basal and maximum MERC index in both replicates. Moreover, we identified 625 tehters and 696 spacers affecting only the basal MERC index; 519 tethers and 67 spacers affecting only the maximum MERC indexes. Protein classes analysis of these three groups of genes by Panther predicted both already known and new protein classes that are yet to explored in terms of ER-mitochondria communication. Subcellular localization analysis to identify predicted proteins to be present in both ER and outer mitochondrial membrane (OMM) of the gene lists detailed before, revealed 13 proteins among the common tethers and spacers, 30 proteins affecting only the basal MERC index and 16 proteins affecting only the maximum MERC index localized on both organelles. One of the protein present in the last group is Leucine Rich Repeat Kinase 2 (LRRK2) and we have further characterized it as ER-mitochondria tether. Subcellular fractionation experiments showed that LRKK2 localized mostly in MAMs. As expected for a tether, levels of ER-mitochondria juxtaposition, measured with FEMP, were decrased in LRRK2-/- MEF. ER-mitochondria proximity was fully restored by reintroduction in MEF LRRK2-/- of wt protein but not of the familial PD associated mutants.
In conclusion, we have developed a new method to assess the proximity between ER and mitochondria and we have utilized this technology to perform two replicates of a high content screen identifying novel structural components of the ER-mitochondria contact sites.

Abstract (italian)

La comunicazione tra organelli cellulari è una caratteristica fondamentale delle cellule eucariotiche ed esercita un ruolo fondamentale in molti processi cellulari. Uno dei processi di comunicazione tra organelli cellulari tra i più caratterizzati è quello dovuto ai siti di contatto tra le membrane di mitocondri e reticolo endoplasmatico (ER). Anche noti come "Mitochondria-associated ER membranes" (MAMs) o "Mitochondria-ER contact sites" (MERCs), la loro esistenza è stata scoperta 50 anni fa tramite studi di microscopia elettronica, ma il loro significato funzionale è iniziato ad emergere solo alla fine degli anni 90 quando è stato dimosdtrato il ruolo dei MERCs nello scambio di calcio dall'ER. Nonostante l'importanza di questi siti di contatto tra organelli sia in fisiologia sia in patologia, solo poche proteine coinvolte nel mantenimento strutturale della distanza tra i due organelli sono state finora identificate nei mammiferi. Mitofusina2 (MFN2) è stato il primo "tether" strutturale ad essere identificato. E' stato rilevato che MFN2 è localizzata sia nella membrana mitocondriale esterna (OMM) sia sulla superficie citosolica dell'ER ed ' in grado di formare intrazioni omo- ed eterotipiche con MFN1, mantenendo quindi la distanza tra i due organelli. Poiché una residua giustapposizione tra i due organelli è stata osservata in cellule MFN2-/-, ulteriori proteine che esercitano questo ruolo devono esistere. Per identificarle, abbiamo stabilito un protocollo ed eseguito due repliche di uno screening genomico su larga scala in fibroblasti embrionali di topo (MEF). Per eseguire questo screening, abbiamo sfruttato un biosensore basato sulla FRET, dove la proteina fluorescente CFP fusa con il dominio funzionale FRB e la proteina fluorescente YFP fusa con il dominio funzionale FKBP vengono fatte localizzare rispettivamente all'ER (grazie alla sequenza di segnale Sac1) ed ai mitocondri (grazie alla sequenza di segnale Akap1) (Csordas G. et al., 2010). Abbiamo modificato questo costrutto inserendo tra i cDNA delle due proteine il peptide autocatalitico Tav2A per ottenere un singolo mRNA e quindi l'espressione equimolare delle due proteine. I domini funzionali FKBP e FRB sono in grado di eterodimerizzare con l'aggiunta di Rapamicina, permettendo così la misurazione non solo dei livelli di giustapposizione basale tra i due organelli, ma anche del massimo livello di contatti che possono avvenire in una cellula. Abbiamo chiamato questo nuovo costrutto FRET ER-mitochondria probe (FEMP). Le caratteristiche uniche del FEMP ci consentono didiscriminare tra le proteine il cui ruolo è quello di mantenere i due organelli vicini, chiamate "tethers", e proteine che invece tengono i due organelli più distanti, definiti "spacers".
Le immagini ottenute dallo screening sono state analizzate e sono stati calcolati due indici, chiamati "basal MERC index" e "maximum MERC index", che rappresentano rispettivamente il livello di contatti osservabili in qualsiasi momento in una cellula e il massimo livello di contatti possibile. A seguito di un'analisi delle immagini automatizzata e di un'analisi statistica effettutata su ~10,000 geni, dopo un processo di selezione abbiamo identificato 205 geni come "tethers" (geni che una volta eliminati aumentano la distanza tra i due organelli) tra mitocondri e ER e 59 geni come "spacers" (geni che una volta eliminati diminuiscono la distanza tra i due organelli) che influenzano sia il basal sia il maximum MERC index in entrambe le repliche. Inoltre, sono stati identificati 625 tethers e 696 spacers che influenzano solo il basal MERC index; e 519 tethers e 67 spacers che modificano solo il maximum MERC index. Analisi delle classi di proteine presenti in questi tre gruppi tramite Panther ha rivelato sia classi di proteine il cui ruolo in questo processo era noto, sia nuove classi di proteine il cui ruolo nella comunicazione tra ER e mitocondri deve ancora essere esplorato. Analisi della localizzazione cellulare per identificare proteine localizzate sia nell'ER sia nei mitocondri delle liste di geni esposte in precedenza, ha rivelato l'esistenza di 13 proteine tra i tethers e gli spacers comuni, 30 proteine che influenzano solo il basal MERC index e 16 proteine che influenzano solo il maximum MERC index localizzate in entrambi gli organelli. Una delle proteine presente nell'ultimo gruppo è "Leucine Rich Repeat Kinase 2" (LRRK2) che abbiamo ulteriormente caratterizzato come tether tra ER e mitocondri. Esperimenti di frazionamento cellulare dimostrano che LRRK2 è localizzata principalmente nelle MAMs. Come previsto per un tether, il livello di prossimità tra ER e mitocondri, misurato tramite FEMP, sono diminuiti in MEF LRRK2-/-. La prossimità tra i due organelli è pienamente recuperata dalla reintroduzione in MEF LRRK2-/- della proteina WT, ma non dei mutanti associati alle forme di Parkinson familiare.
In conclusione, abbiamo sviluppato un nuovo metodo per determinare la prossimità tra ER e mitocondri e abbiamo utilizzato questa tecnologia per eseguire due repliche di uni screening gnomico su larga scala identificando nuovi componenti strutturali dei contatti tra mitocondri e ER.

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EPrint type:Ph.D. thesis
Tutor:Bernardi, Paolo
Supervisor:Scorrano, Luca
Ph.D. course:Ciclo 29 > Corsi 29 > BIOSCIENZE E BIOTECNOLOGIE
Data di deposito della tesi:13 January 2017
Anno di Pubblicazione:13 January 2017
Key Words:mitocondri/mitochondria, reticolo endoplasmatico/ endoplasmic reticulum, FRET, MAMs, organelle contact sites, parkinson
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:9840
Depositato il:02 Nov 2017 15:12
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