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Filograna, Roberta (2015) Superoxide radical dismutation as protective mechanism to hamper the progression of Parkinson's disease. [Ph.D. thesis]

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Abstract (english)

Parkinson's disease (PD) is a degenerative neurological syndrome characterized by the preferential loss of dopaminergic (DAergic) neurons in the Substantia Nigra pars compacta. PD is still incurable and conventional therapies treat only symptoms to improve the quality of life. Therefore, there is a impelling need to find out new therapeutic strategies that not only provide symptomatic relief but also halt or reverse the neuronal damage hampering PD progression. Even though the pathogenesis of this disorder remains poorly understood, oxidative stress has been identified as one of the major contributors for the nigral loss in both sporadic and genetic forms of the disease. In particular, the selective vulnerability of DAergic neurons to oxidative stress might be ascribed to dopamine (DA) metabolism, which occurs in the cytosol and represents in itself a relevant pathway for superoxide radicals production. The main hypothesis of this thesis is that the inhibition of reactive oxygen species (ROS) overproduction might delay, block or prevent the degenerative process that occurs in PD patients. In this scenario, our project was addressed to study in vitro and in vivo the potential protective role of the superoxide dismutase (SOD) enzymes and SOD mimetic compounds against oxidative injury, related to PD, adopting two experimental paradigms. We focused on SODs because they exert a crucial function in cellular antioxidant defense, promoting the elimination of superoxide anion.
The first experimental paradigm was represented by the herbicide paraquat (PQ) whose mechanism of action relies on the production of oxidative stress and it is epidemiologically linked to sporadic PD. The second one, which has been used to model a familial form of PD, was based on PINK1 deficiency. Indeed, PINK1 gene mutations have been identified as cause of recessive early-onset parkinsonism. This gene encodes for a serine/threonine kinase that is involved in the mitochondrial quality control and in the regulation of cellular oxidative status.
To evaluate whether SODs might have a protective activity against PQ toxicity or PINK1 deficiency, the cytosolic and mitochondrial SODs, respectively SOD1 and SOD2, were overexpressed in the human neuroblastoma SH-SY5Y cells and in Drosophila melanogaster. In cells and flies, the overexpression of the mitochondrial isoform rescued acute PQ toxicity. The selective effect observed seems to be associated to an intrinsic mechanism of acute treatment, which strongly compromise mitochondria, increasing ROS in these organelles and promoting their fragmentation. On the contrary, in flies the cytosolic isoform ameliorated motor dysfunctions induced by a chronic PQ exposure, even when SOD1 was overexpressed exclusively into the DAergic neurons. These observations indicate that the cytosolic compartment is particularly affected by chronic PQ treatment suggesting that other oxidative processes in the cytosol of DAergic cells, such as DA metabolism, might amplify PQ-induced oxidative stress making them particularly vulnerable. In SH-SY5Y cells, PINK1 deficiency resulted in mitochondrial fragmentation. Even in this case, SODs appeared protective rescuing the phenotype. However, while SOD1 overexpression slightly reduced these mitochondrial alterations, SOD2 seemed to reverse mitochondrial fragmentation allowing the maintenance of a healthy mitochondrial network. In flies, loss of PINK1 induced a severe motor impairment, which was rescued only by the overexpression of the cytosolic isoform suggesting that the protein might be involved in other pathways that are not strictly correlated with mitochondrial functioning.
Once the beneficial activity of SODs has been demonstrated, we then investigated the therapeutic potential use of a SOD-mimetic compound, M40403. We found that the molecule was able to protect cells and flies against the oxidative damage induced by both acute and chronic PQ exposure. In addition, the SOD mimetic was effective also in PINK1 deficient cells and flies reducing, respectively, mitochondrial fragmentation and locomotor defects. Finally, M40403 administration in SOD1 and SOD2 deficient flies partially replaced the loss of both isoforms suggesting that it can act at cytosolic and mitochondrial level.
Overall, these findings demonstrate that specific SOD-mimetic compounds can be efficacious in reducing oxidative stress and should be further explored as therapeutic agents to hamper the progression of PD.
In parallel, we developed a second research line which was aimed to the characterization of two human neuroblastoma cell lines in order to identify, between them, the most reliable cellular model for PD studies.
Cellular models are largely used to study in vitro the molecular mechanisms underlying DAergic degeneration in PD. Although their use presents several advantages, cell lines do not always recapitulate morphological and neurochemical properties of DAergic neuronal cells. Considering the relevance of DA metabolism in the pathogenesis of PD, the DAergic phenotype is an important requirement. Human neuroblastoma cell lines are commonly used as models in PD research, although they are undifferentiated, do not exhibit markers of mature neurons and appear able to synthetize different neurotransmitter, in particular the catecholamines DA and noradrenaline (NA). For this reason, we studied the ability of three different agents, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), retinoic acid (RA) and staurosporine to drive neuronal differentiation toward a DAergic phenotype in SH-SY5Y and BE(2)-M17 cells. The first cell line is largely adopted and studied, even though the phenotype acquired upon differentiation is still a debated issue. In contrast, the second one is poorly characterized and might represent a valid alternative cellular system. In this thesis, we first investigated the acquisition of neuronal-like features in terms of growth inhibition, cell morphology and neuronal markers expression. Our results indicated that staurosporine and RA were the most efficient treatments to inhibit cell growth, respectively in SH-SY5Y and BE(2)-M17. Furthermore, in both cell lines, RA and staurosporine promoted the formation a complex network of neuritic extensions and the expression of mature neuronal markers. To evaluate whether the differentiation promotes a DAergic or NAergic phenotype in these cell lines, we analyzed the expression profile of the major genes involved in DA and NA metabolism and the intracellular content of these neurotransmitters. In SH-SY5Y cells, RA and TPA induced the down-regulation of DA- and NA-related genes as well as a decrease of neurotransmitter amounts compared to undifferentiated cells, indicating the loss of the catecholaminergic phenotype. On the contrary, staurosporine treatment resulted in the up-regulation of all these genes and an increase of NA content, enhancing the NAergic phenotype. Surprisingly, in BE(2)-M17, DA and NA levels detected in undifferentiated cells were considerably more elevated than in SH-SY5Y which suggests that these cells presents a more pronounced catecholaminergic phenotype. The latter was not affected by TPA and RA treatments, which did not substantially alter gene expression and the amount of neurotransmitters. In contrast, staurosporine promoted the up-regulation of the genes involved in metabolism of DA and NA and an increase of their intracellular amounts, indicating a relevant enhancement of the observed phenotype.
These results indicate that the BE(2)-M17 cell line emerges as a new experimental model with a catecholaminergic phenotype that differs substantially from those of SH-SY5Y cells, suggesting different fields of application for the two cell lines

Abstract (italian)

La malattia di Parkinson è una sindrome neurologica degenerativa, caratterizzata dalla perdita preferenziale dei neuroni dopaminergici della Substantia Nigra pars compacta. Questa patologia è attualmente incurabile e le terapie convenzionali agiscono esclusivamente sui sintomi migliorando la qualità della vita. Pertanto, è necessario identificare nuove strategie terapeutiche che non solo forniscano un efficacie trattamento della sintomatologia ma agiscano anche ritardando i danni neuronali e arrestando la progressione della malattia. Sebbene l'eziologia è tuttora sconosciuta, lo stress ossidativo sembra svolgere un ruolo chiave nella degenerazione dopaminergica sia nella forme sporadiche che familiari della patologia. In particolare, la selettiva vulnerabilità di tali neuroni allo stress ossidativo potrebbe essere associata al metabolismo della dopamina (DA), evento molecolare citosolico responsabile, esso stesso, della sovrapproduzione di specie reattive dell'ossigeno (ROS) L'ipotesi principale alla base di questa tesi è che l'inibizione della produzione di ROS possa ritardare, arrestare o prevenire il processo neurodegenerativo che si verifica nei pazienti affetti dal morbo di Parkinson. In questo scenario, il nostro progetto si propone di studiare in vitro e in vivo il potenziale ruolo protettivo delle superossido dismutasi (SOD) e di composti che ne mimano l'attività (SOD mimetici) contro i danni ossidativi, correlati a tale patologia, utilizzando due diversi paradigmi sperimentali. La scelta di studiare questi enzimi è legata alla loro funzione cellulare antiossidante, cruciale nel promuovere l'eliminazione dell'anione superossido, radicale capostipite nella produzione a valle di specie molto pi๠tossiche e reattive.
In questo studio, il primo paradigma utilizzato è l'erbicida paraquat (PQ), il cui meccanismo di tossicità si basa sulla produzione di stress ossidativo. L'esposizione cronica a tale molecola è stata correlata epidemiologicamente all'insorgenza delle forme sporadiche di Parkinson. Il secondo modello adottato si basa sulla deficienza della chinasi PINK1, responsabile di una forma familiare della malattia. Infatti, mutazioni a carico del gene PINK1 sono state identificate come causa di parkinsonismo giovanile precoce. Questa proteina sembra svolgere un ruolo chiave nel mitochondrial quality control e nella regolazione dello stress ossidativo.
Al fine di studiare la potenziale azione protettiva delle SOD contro la tossicità esercitata dal PQ o indotta dall'assenza di PINK1, l'isoforma citosolica e quella mitocondriale, rispettivamente SOD1 e SOD2, sono state sovraespresse nelle cellule di neuroblastoma umano SH-SY5Y e in Drosophila melanogaster. In vitro e in vivo, esclusivamente la sovraespressione dell'isoforma mitocondriale ha evidenziato un effetto protettivo contro l'esposizione acuta al PQ. La selettività osservata potrebbe essere associata ad un meccanismo di tossicità intrinseco dell'erbicida che, ad elevate dosi, comprometterebbe fortemente i mitocondri, aumentando la produzione di ROS in questi organelli e promuovendone la frammentazione. Al contrario, in Drososphila, l'enzima citosolico SOD1 è in grado di migliorare le performance motorie, alterate dall'esposizione cronica al PQ. Tale effetto è stato rilevato anche quando la sovraespressione era indotta esclusivamente a livello dei neuroni dopaminergici. Le nostre osservazioni indicano che in tali condizioni il compartimento citosolico potrebbe essere particolarmente compromesso, suggerendo che nei neuroni dopaminergici il citosol possa essere la sede di altri meccanismi ossidativi, tra i quali il metabolismo della DA, in grado di amplificare o esacerbare lo stress ossidativo indotto dal PQ, rendendo tali cellule particolarmente vulnerabili. In cellule SH-SY5Y, la deficienza di PINK1 ha causato un fenotipo mitocondriale caratterizzato dalla frammentazione del network di questi organelli. Anche in questo caso, le SOD hanno svolto una funzione protettiva contrastando la frammentazione mitocondriale osservata. Tuttavia, mentre la sovraespressione della SOD1 ha ridotto solo parzialmente il danno, la SOD2 è apparsa in grado di garantire il mantenimento di un corretto network mitocondriale. In Drosophila, la perdita di PINK1 promuove una severa disabilità motoria, la quale puಠessere migliorata dall'attività dell'isoforma citosolica SOD1, suggerendo che PINK1 possa essere coinvolta in altri processi molecolari non strettamente correlati col mantenimento del funzionamento mitocondriale.
Dimostrata l'azione protettiva delle SOD, abbiamo deciso di studiare il potenziale utilizzo terapeutico del SOD mimetico M40403. I risultati delle nostre analisi hanno evidenziato che tale molecola svolga un'attività antiossidante, in vitro e in vivo, proteggendo dal danno ossidativo indotto dal trattamento acuto e cronico con l'erbicida PQ. Inoltre, il composto M40403 è stato testato in modelli cellullari e animali privi di PINKI1 nei quali ha migliorato, rispettivamente, il fenotipo mitocondriale e i difetti nell'apparato locomotore. Infine la somministrazione di questo SOD mimetico in linee di Drosophila deficienti per SOD1 o SOD2, ha rivelato che la molecola possa sopperire parzialmente all'assenza di ciascun enzima, supportando l'ipotesi che possa agire sia a livello citosolico che mitocondriale.
Complessivamente, i dati ottenuti finora hanno dimostrato che l'utilizzo di specifici composti SOD mimetici, in particolare M40403, possa essere efficacie nel contrastare danni ossidativi. Questi composti dovrebbero essere ulteriormente studiati al fine di identificare un possibile agente terapeutico per la malattia di Parkinson.
Parallelamente al progetto appena descritto, ci siamo focalizzati su un seconda linea di ricerca volta alla caratterizzazione dei due linee di neuroblastoma umano al fine di definire quali, tra queste, rappresenti il modello cellulare pi๠attendibile per lo studio della malattia di Parkinson.
I modelli cellulari sono largamente utilizzati nello studio in vitro dei meccanismi molecolari alla base della degenerazione dei neuroni dopaminergici. Nonostante il loro utilizzo presenti grandi vantaggi, queste linee cellulari non sempre ricapitolano le proprietà morfologiche e neurochimiche dei suddetti neuroni. Pertanto, considerando il ruolo del metabolismo della DA nell'eziologia del morbo di Parkinson, l'acquisizione del fenotipo dopaminergico risulta essere un requisito importante. In particolare, le linee cellulari di neuroblastoma sono spesso usate come modello, nonostante siano proliferanti, non esprimano markers caratteristici dei neuroni maturi e siano in grado di sintetizzare diversi neurotrasmettitori, in particolare le catecolamine DA e noradrenalina (NA). Per queste ragioni, abbiamo studiato l'abilità di tre differenti agenti, il 12-O-tetradecanoilforbolo-13-acetato (TPA), l'acido retinoico (RA) e la staurosporina, nel guidare il differenziamento delle cellule SH-SY5Y e BE(2)-M17 verso un fenotipo dopaminergico. La prima di queste linee cellulari è ampiamente utilizzata e studiata, nonostante il fenotipo acuisito dopo il differenziamento sia ancora un argomento dibattuto. Al contrario, la seconda è stata finora poco caratterizzata e potrebbe rappresentare un valido sistema cellulare alternativo.
In questa tesi, al fine di valutare l'acquisizione delle caratteristiche neuronali, abbiamo inizialmente analizzato l'effetto indotto dai tre agenti sull'inibizione della crescita, morfologia cellulare e espressione di markers neuronali. I nostri risultati hanno dimostrato che il trattamento con staurosporina e RA siano i pi๠efficienti nell'arrestare la proliferazione cellulare rispettivamente nelle cellule SH-SY5Y e BE(2)-M17. Inoltre, in entrambe le linee, RA e staurosporina promuovono la formazione di un compresso network di ramificazioni neuritiche e l'espressione di specifici markers neuronali citoscheletrici. Per studiare l'effetto del differenziamento nell'acquisizione di un fenotipo dopaminergico o noradrenergico nei due modelli cellulari, abbiamo valutato il profilo di espressione dei geni principalmente coinvolti nella sintesi di entrambi i neurotrasmettitori e i loro contenuto intracellulare. In cellule SH-SY5Y, il trattamento con RA e TPA è risultato in grado di promuovere non solo la down-regolazione dei geni analizzati ma anche una consistente riduzione del contenuto di DA e NA, suggerendo la perdita del fenotipo catecolaminergico. Al contrario, la staurosporina ha evidenziato la capacità di up-regolare l'espressione genica degli enzimi coinvolti nella sintesi dei due neurotrasmettitori e di incrementare il contenuto di NA, amplificando il fenotipo noradrenergico di questo modello. Nella linea cellulare BE(2)-M17, i livelli di DA and NA rilevati prima del differenziamento risultano essere considerevolmente elevati rispetto a quelli misurati nelle SH-SY5Y, evidenziando che la prima abbia un fenotipo catecolaminergico molto pi๠pronunciato della seconda. Quest'ultimo non viene sostanzialmente alterato dai trattamenti con TPA e RA, mentre il differenziamento con staurosporina è nuovamente in grado di up-regolare il profilo di espressione analizzato e di promuovere un'ulteriore sintesi di DA e NA, determinando l'acquisizione di un fenotipo ulteriormente marcato.
Concludendo, i risultati di questo studio indicano che la linea BE(2)-M17 possa essere un modello sperimentale alternativo con proprietà neurochimiche differenti dalle SH-SY5Y, suggerendo l'applicazione delle due line cellulari in differenti campi di ricerca.

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EPrint type:Ph.D. thesis
Tutor:Beltramini, Mariano
Supervisor:Bisaglia, Marco
Data di deposito della tesi:01 February 2015
Anno di Pubblicazione:02 February 2015
Key Words:SOD mimetici, malattia di Parkinson/SOD mimetic compounds, Parkinson's disease
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/09 Fisiologia
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:7926
Depositato il:12 Nov 2015 09:40
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