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Basso, Valentina (2018) Regulation of ER-Mitochondria tethering in an in vivo animal model of Parkinson's disease. [Ph.D. thesis]

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Abstract (english)

Mitochondria form a tubular, reticulated network which shape is controlled by opposing fusion and fission events (Bereiter-Hahn and Voth, 1994). The mitofusins 1 and 2 (Mfn1 and Mfn2) are conserved, dynamin-like GTPases embedded in the outer mitochondrial membrane (OMM) that mediate mitochondrial fusion in coordination with OPA1 (Rojo et al., 2002; Santel and Fuller, 2001; Wong et al., 2000). Mitochondrial shaping proteins have pleiotropic functions. In particular, while Mfn1 seems primarily involved in organellar docking and fusion, Mfn2 is enriched at contact sites between ER and mitochondria where it is implicated in the formation of molecular linkers that are capable of organelles tethering (Chen et al., 2012; de Brito and Scorrano, 2008). Recent works attributed to these points of close contact between the OMM and the nearby ER, called MAMs (mitochondria-associated ER-membranes) or MERCs (mitochondria-ER contacts), an important role in the propagation of cellular signals, including those that control lipid metabolism, calcium (Ca2+) homeostasis and cell death (Rowland et al., 2012; Rizzuto et al., 1998; Vance, 1990). Indeed, aberrations in ER-mitochondria juxtaposition have been described in cellular models of different neurodegenerative diseases, including Alzheimer's, Huntington's and Parkinson's disease (Krols et al., 2016; Calì et al., 2013; Ottolini et al., 2013; Area-Gomez et al., 2012; Calì et al., 2012; Panov et al., 2002). Although the exact cause for neuronal loss is not clear
Parkin, an E3-ubiquitin ligase mutated in familiar Parkinson's Disease (PD) is selectively recruited to dysfunctional mitochondria and promotes their elimination via autophagy, a process known as mitophagy (Narendra et al., 2008). PINK1, a protein kinase, also a PD related gene, is required for Parkin recruitment and stress induced mitophagy (Ziviani et al., 2010). In several model systems, Parkin selectively ubiquitinates the mitochondrial outer membrane profusion protein Mfn1 and Mfn2 and fly homologue Marf (Tanaka et al., 2010; Ziviani et al., 2010; Gegg et al., 2010). Accordingly, lack of Parkin or PINK1, which operates upstream Parkin in the same pathway, results in impaired ubiquitination of Mfn and increased levels of Mfn (Ziviani et al., 2010).
Given that Parkin affects Mfn steady state and ubiquitination levels, we propose to (i) address the ubiquitination levels of Mfn2 and whether Parkin downregulation affects it; (ii) investigate whether Parkin regulates ER-mitochondria tethering by impinging on Mfn2 steady state and ubiquitination levels; (iii) evaluate the physiological significance of ER-mitochondria interaction in an in vivo animal model of Parkinson's disease.
Our hypothesis is that Parkin dependent Mfn ubiquitinatination controls ER-mitochondria tethering, thus impinging on Ca2+ transfer and Ca2+ homeostasis, which dysregulation has been described in a number of molecular pathways leading to PINK1 and Parkin loss of function dependent neurodegeneration (Calì et al., 2013; Ottolini et al., 2013; Calì et al., 2012).
In order to address the previously listed hypothesis we analysed the pattern of ubiquitination of Mfn2 in mouse embryonic fibroblasts (MEFs) upon downregulation of Parkin. To this aim, we (i) immunoprecipitated Mfn2 with specific anti Mfn2 antibody and performed western blotting analysis with specific anti HA antibody in cells overexpressing HA tagged Ubiquitin; (ii) measured the degree of tethering between ER and mitochondria in control and Parkin downregulating cells. We used two independent approaches to measure ER-mitochondria tethering: we first measured the percentage of ER co-localizing with mitochondria by using Mander's coefficient of co-localization upon volume-rendered 3D reconstruction of z-axis stacks of confocal images of cells expressing organelles targeted fluorescence probes (mito-RFP and ER-YFP, respectively) (Rizzuto et al., 1998). Secondly, we took advantage of a FRET based probe (Naon et al., 2016) to measure ER-mitochondria proximity. In this sensor, called FEMP, FRET intensity is inversely proportional to the distance between the two fluorophores (mito-YFP and ER-CFP) that are appropriately targeted to the two compartments. (iii) We investigated the physiological significance of ER-mitochondria tether in an in vivo animal model of PD that lacks PINK1 expression. To this aim we used the fruitfly Drosophila melanogaster, which has many advantages. First, fly mutants deriving from loss of function mutations of PINK1 have been extensively characterized and cause a robust phenotype represented by age-related degeneration of DA neuron loss and locomotor deficits (Poole et al., 2008; Clark et al., 2006; Park et al., 2006; Yang et al., 2006; Wang et al., 2006). Secondly, a variety of genetic modifications and epistasis experiments can be easily performed in vivo to dissect molecular pathways.
Our results showed that Parkin downregulation reduced Mfn ubiquitination and ER-mitochondria tethering in MEFs. Interestingly, we found that the pattern of Mfn2 ubiquitination and ER-mitochondria tethering is also impaired in CMT type 2A disease-associated Mfn2 mutations (Mfn2R94Q, Mfn2P251A and Mfn2R280H respectively). Although indirectly, these findings strongly suggested that ubiquitination of Mfn2, rather than its steady state levels, is important in the regulation of ER-mitochondria tethering.
To identify the precise site of Mfn2 ubiquitination and directly link lack of ubiquitination with impaired ER-mitochondria tether, we took advantage of a bioinformatics approach to identify among species-highly conserved lysine (K) residues. We identified twenty Lysine residues that were conserved between human, mouse and fly. We compared these residues with those identified by a mass spectrometry-based study published in 2014 (Bingol et al., 2014) that identified Parkin-dependent ubiquitination sites. We identified six Lysine residues that were likely to represent good candidates for Parkin-dependent ubiquitination of Mfn2. We generated non-ubiquitinatable mutants for those sites by substituting Lysine (K) with Arginine (R), a common procedure to impair ubiquitination and investigated the pattern of ubiquitination of the non-ubiquitinatable Mfn2 mutants by western blotting. Expression of non-ubiquitinable mutant K416R resulted in impaired Mfn2 ubiquitination. Of note this mutant was also unable to correct ER-mitochondrial contacts when expressed in Mfn2 KO MEFs and only partial restored ER-mitochondrial Ca2+ transfer.
In summary, our results provided strong evidences that Mfn2 ubiquitination is a prerequisite for ER-mitochondria physical and functional interaction and that K416 in the HR1 domain of Mfn2 is a genuine site for Parkin dependent ubiquitination.
A number of studies have shown impaired Ca2+ homeostasis in cellular models lacking PINK1 or Parkin (Heeman et al., 2011; Sandebring et al., 2009). Although it is not clear why dopaminergic neurons specifically degenerate in PD, it is tempting to hypothesis that impaired Ca2+ homeostasis resulting from impaired Ca2+ cross talk at ER-mitochondria interface could lead or contribute to degeneration. Elegant studies have shown that artificial tether between ER and mitochondria can be used to modulate Ca2+ transfer (Csordas et al., 2010; Csordas et al., 2006). With that in mind, we addressed whether expressing an ER-mitochondria synthetic linker in a well-established in vivo Drosophila model of PINK1 loss of function could ameliorate PINK1 KO phenotypes by impinging on ER-mitochondria cross talk. We therefore generated a number of fly lines expressing the synthetic linker driven by a neuron-specific driver in the fly wing neurons. This linker was generated by Csordas et al. (Csordas et al., 2006) and consists of a monomeric fluorescent protein (RFP) fused to the outer mitochondrial membrane targeting sequence at the N terminus and fused to the ER targeting sequence at the C terminus. We could observe a well-defined and easily quantifiable RFP-fluorescence spots throughout the L1 vein of the fly wing that perfectly matched the morphology seen when expressing mito-GFP or ER-GFP alone in the wing neurons (Vagnoni and Bullock, 2016), which indicated that the synthetic linker was appropriately expressed.
Interestingly, we found an amelioration of PINK1 KO climbing ability upon expression of the artificial synthetic linker. This result strong indicates that restoration of proper ER-mitochondrial communication in PINK1 KO background can be beneficial in ameliorating the phenotype associated to an in vivo animal model of PD, paving the way for novel approaches for medical intervention.

Abstract (italian)

I mitocondri formano un network reticolare e tubulare la cui forma è controllata da eventi opposti di fusione e fissione (Bereiter-Hahn and Voth, 1994). Le mitofusine 1 e 2 (Mfn1 e Mfn2), sono delle GTPasi dynamin-like incorporate nella membrana mitocondriale esterna (OMM, outer mitochondrial membrane) e mediano la fusione mitocondriale in cooperazione con OPA1 (Rojo et al., 2002; Santel and Fuller, 2001; Wong et al., 2000). Le shaping protein mitocondriali hanno una funzione pleiotropica. In particolare, mentre la Mfn1 sembra principalmente coinvolta nel docking e nella fusione di organelli, la Mfn2 è arricchita nei punti di contatto tra ER e mitocondri dove è implicata nella formazione di collegamenti molecolari che sono capaci di produrre un'interazione tra gli organelli (Chen et al., 2012; de Brito and Scorrano, 2008). Lavori recenti attribuiscono a questi punti di stretto contatto tra l'OMM e il vicino ER, chiamati MAMs (mitochondria-associated ER-membranes) o MERCS (mitochondria-ER contacts), un importante ruolo nella propagazione del segnale cellulare, incluso quello che controlla il metabolismo lipidico, l'omeostasi del calcio (Ca2+) e la morte cellulare (Rowland et al., 2012; Rizzuto et al., 1998; Vance, 1990). Un'anomalia nella comunicazione tra ER e mitocondri è stata descritta in vari modelli cellulari di differenti malattie neurodegenerative, che includono la malattia di Alzheimer, Huntington e Parkinson (Krols et al., 2016; Calì et al., 2013; Ottolini et al., 2013; Area-Gomez et al., 2012; Calì et al., 2012; Panov et al., 2002). Tuttavia la causa esatta che induce la perdita neuronale non è ancora conosciuta.
Parkin, una E3-ubiquitina ligasi mutata nelle forme familiari di malattia di Parkinson (PD, Parkinson's disease) è selettivamente reclutata sui mitocondri disfunzionali e promuove la loro eliminazione tramite autofagia, un processo conosciuto come mitofagia (Narendra et al., 2008). PINK1, una proteina chinasica e gene associata alla PD, è richiesto per il reclutamento di Parkin e per la mitofagia indotta da stress (Ziviani et al., 2010). Nei diversi sistemi modello, Parkin ubiquitina selettivamente le proteine ancorate sulla membrana mitocondriale esterna che promuovono la fusione (Mfn1 e Mfn2) e il loro omologo in Drosophila (Marf) (Tanaka et al., 2010; Ziviani et al., 2010; Gegg et al., 2010). Di conseguenza, l'assenza di Parkin o PINK1, il quale opera a monte di Parkin nella stessa pathway, causa un'alterazione nell'ubiquitinazione della Mfn e un aumento dei livelli di Mfn (Ziviani et al., 2010).
Dato che Parkin altera i livelli basali e di ubiquitinazione della Mfn, noi abbiamo proposto di (i) valutare i livelli di ubiquitinazione della mitofusina ed analizzare se la downregolazione di Parkin ha effetti su questi livelli; (ii) investigare se Parkin regola il legame tra ER e mitocondri andando ad agire sui livelli stazionari o di ubiquitinazione della Mfn2; (iii) valutare il significato fisiologico dell'interazione ER-mitocondri in un modello animale in vivo di malattia di Parkinson.
La nostra ipotesi è che l'ubiquitinazione della Mfn Parkin-dipendente controlli il legame ER-mitocondri, interferendo così con il trasferimento e l'omeostasi di Ca2+, la cui alterazione è stata descritta in numerose pathway molecolari che causano neurodegenerazione associata alla perdita di funzionalità  di PINK1 e Parkin (Calì et al., 2013; Ottolini et al., 2013; Calì et al., 2012).
Al fine di affrontare la precedente lista di ipotesi abbiamo analizzato i livelli di ubiquitinazione della Mfn2 in fibroblasti embrionali di topo (MEFs: mouse embryonic fibroblasts) in seguito alla downregolazione di Parkin. A questo scopo, abbiamo (i) immunoprecipitato la Mfn2 con lo specifico anticorpo anti Mfn2 ed eseguito il western blotting con lo specifico anticorpo anti HA in cellule overesprimenti l'ubiquitina taggata HA; (ii) misurato i livelli di connessione tra ER e mitocondri nelle cellule di controllo e in cellule con Parkin downregolato. Abbiamo utilizzato due approcci indipendenti per misurare questa connessione: per prima cosa abbiamo misurato la percentuale di co-localizzazione dell'ER con i mitocondri usando il coefficiente di co-localizzazione di Mander in seguito alla ricostruzione volumetrica 3D delle immagini confocali lungo l'asse z di cellule esprimenti le sonde fluorescenti bersaglio degli organelli (rispettivamente, mito-RFP and ER-YFP) (Rizzuto et al., 1998). In secondo luogo, abbiamo sfruttato una sonda basata su FRET (Naon et al., 2016) per misurare la vicinanza dell'ER con i mitocondri. In questo sensore, chiamato FEMP, l'intensità  di FRET è inversamente proporzionale alla distanza tra i due fluorofori (mito-YFP e ER-CFP) che sono opportunamente indirizzati ai due compartimenti. (iii) Abbiamo studiato il significato fisiologico dell'interazione ER-mitocondrio in un modello animale in vivo di PD privo dell'espressione di PINK1. A questo scopo abbiamo usato la Drosophila melanogaster, che ha molti vantaggi. Innanzitutto i mutanti di Drosophila, derivati da mutazioni che causano la perdita di funzionalità  di PINK1, sono stati ampiamente caratterizzati ed inducono un fenotipo robusto rappresentato dalla perdita dei neuroni DA e deficit locomotori correlati all'età  (Poole et al., 2008; Clark et al., 2006; Park et al., 2006; Yang et al., 2006; Wang et al., 2006). In secondo luogo, in vivo possono essere facilmente eseguiti un'ampia varietà  di modifiche genetiche ed esperimenti di epistasi per comprendere più approfonditamente le pathway molecolari.
I nostri risultati mostrano che in MEFs la downregolarione di Parkin riduce l'ubiquitinazione della Mfn e l'interazione tra ER e mitocondri. Abbiamo osservato inoltre che le mutazioni della Mfn2 associate a CMT di tipo 2A (rispettivamente Mfn2R94Q, Mfn2P251A e Mfn2R280H) causano l'alterazione dei livelli di ubiquitinazione della Mfn2 ed una diminuzione nell'interazione tra ER e mitocondri. Sebbene indirettamente, questi risultati suggeriscono fortemente che l'ubiquitinazione della Mfn2, piuttosto che i livelli stazionari, è importante nella regolazione dell'interazione tra ER e mitocondri.
Per identificare il sito preciso di ubiquitinazione della Mfn2 e correlare direttamente la mancanza dell'ubiquitinazione con la riduzione dell'interazione ER-mitocondri, abbiamo sfruttato un approccio bioinformatico che ci ha permesso di individuare i residui di lisina (K) altamente conservate nelle varie specie. Abbiamo identificato venti residui di lisina che sono conservati tra uomo, topo e Drosophila. Abbiamo confrontato questi residui con quelli descritti in uno studio basato sull'utilizzo della spettrometria di massa per identificare i siti di ubiquitinazione dipendenti da Parkin pubblicato nel 2014 (Bingol et al., 2014). Abbiamo identificato sei residui di lisina che potrebbero rappresentare dei buoni candidati per l'ubiquitinazione Parkin-dipendente della Mfn2. Abbiamo generato i mutanti non ubiquitabili per questi siti sostituendo la lisina (K) con l'arginina (R), una procedura comune per bloccare l'ubiquitinazione e studiato il pattern di ubiquitinazione dei mutanti Mfn2 non ubiquitinabili mediante western blotting.
L'espressione del mutante non ubiquitinabile K416R ha provocato un'alterazione dell'ubiquitinazione della Mfn2. Da notare che questo mutante non è stato in grado di ripristinare i contatti ER-mitocondri quando reintrodotto in MEF Mfn2 KO ed ha restaurato solo parzialmente il trasferimento di Ca2+ ER-mitocondriale. In breve, i nostri risultati hanno fornito prove evidenti che l'ubiquitinazione di Mfn2 è un prerequisito per l'interazione fisica e funzionale dei mitocondri con l'ER e che la K416 nel dominio HR1 della Mfn2 è un vero e proprio sito per l'ubiquitinazione Parkin-dipendente.
Vari studi hanno osservato in diversi modelli cellulari privi di PINK1 o Parkin un'alterata omeostasi del Ca2+ (Heeman et al., 2011; Sandebring et al., 2009). Sebbene non sia chiaro il motivo per il quale nel PD degenerino specificatamente i neuroni dopaminergici è allettante ipotizzare che un deficit nell'omeostasi del Ca2+, risultante da un alterato scambio di Ca2+ nell'interfaccia ER-mitocondrio, possa portare o contribuire alla degenerazione. Eleganti studi hanno dimostrato che un legame artificiale tra ER e mitocondri può essere usato per modulare il trasferimento di Ca2+ (Csordas et al., 2010; Csordas et al., 2006). Tenendo questo a mente, ci siamo occupati del fatto che l'espressione di un legante sintetico tra ER e mitocondri in un modello in vivo di Drosophila PINK1 loss of function potesse migliorare il fenotipo dei PINK1 KO incidendo sulla comunicazione ER-mitocondriale. Per questo motivo abbiamo generato un certo numero di linee di Drosophila esprimenti il linker sintetico guidato da uno specifico driver neuronale nei neuroni delle ali. Questo linker è stato generato da Csordas et al. (Csordas et al., 2006) e consiste in una proteina monomerica fluorescente (RFP) fusa all'N terminale con la sequenza bersaglio della membrana mitocondriale esterna e fusa al C-terminale con la sequenza bersaglio dell'ER. Abbiamo potuto visualizzare e quantificare i punti di fluorescenza RFP lungo la vena L1 nell'ala della Drosophila dimostrando una corrispondenza con la morfologia osservata a seguito dell'espressione di mito-GFP o ER-GFP sui neuroni dell'ala (Vagnoni e Bullock, 2016), indice del fatto che l'espressione del linker sintetico era appropriata.
E' interessante notare che abbiamo osservato un miglioramento dell'abilità  di arrampicata della Drosophila PINK1 KO in seguito all'espressione del linker sintetico artificiale. Questo risultato indica che il ripristino della corretta comunicazione tra ER e mitocondri nel background PINK1 KO può essere utile per migliorare il fenotipo associato ad un modello animale in vivo di PD, aprendo la strada a nuovi approcci per l'intervento medico.


EPrint type:Ph.D. thesis
Tutor:Ziviani, Elena
Ph.D. course:Ciclo 30 > Corsi 30 > BIOSCIENZE
Data di deposito della tesi:15 January 2018
Anno di Pubblicazione:15 January 2018
Key Words:Mitochondria, Parkinson's disease, ER-mitochondria tethering, Mitofusin, Parkin, PINK1, ubiquitination, ER-mitochondria synthetic tether, Drosophila model of PD.
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:10786
Depositato il:08 Nov 2018 11:08
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