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Norante, Rosa Pia (2017) Studying alterations of Ca2+ homeostasis in in vitro cell models of Amyotrophic Lateral Sclerosis. [Tesi di dottorato]

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Abstract (inglese)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective death of motor neurons (MNs). The mechanism of MN demise, however, is poorly understood, and no effective treatment is yet available. In most cases ALS occurs sporadically, but 10% of cases show a familial history and about 20% of these familial ALS (fALS) are caused by a mutation in the superoxide dismutase 1 (SOD1) gene. In particular, expression of the fALS-related SOD1(G93A) mutant in transgenic (Tg) mice closely resembles human disease. Recent research has found that mutant SOD1 (mSOD1) alters Ca2+ homeostasis in MNs and neighbouring astrocytes, thereby rendering MNs particularly vulnerable to the activation of a subset of harmful pathways. Such notions prompted us to compare local Ca2+ movements in spinal MNs and astrocytes from SOD1(G93A) and SOD1(WT) mice. To this purpose, we applied two different approaches. 1. Analysis of local Ca2+ fluxes in MNs. i) We initially set the conditions for establishing MN-rich primary cultures from Tg mouse spinal cord;
ii) we engineered and produced adeno-associated viral (AAV) vectors for the expression of cameleon Ca2+ probes targeted to different cellular compartments, under the control of a MN-specific (Hb9-derived) promoter;
iii) we functionally tested and successfully used such Ca2+ probes for imaging Ca2+ oscillations in primary spinal cord MNs, demonstrating a specific expression in MNs and a higher Ca2+ entry in the cytosol through AMPA stimulation in SOD1(G93A) MNs compared to controls. We demonstrated also that this probes can also be expressed in vivo in spinal cord MNs upon systemic administration to newborn mice.
2. Analysis of local Ca2+ fluxes and related parameters in spinal astrocytes.
Following the notion that astrocytes affect disease progression in fALS Tg mice, we have also undertaken a thorough comparative investigation of local Ca2+ homeostasis in primary spinal astrocytes from SOD1(G93A) and SOD1(WT) mice to determine if mSOD1 impairs astrocyte Ca2+ homeostasis.
i) We initially set the conditions for the expression of locally targeted Ca2+ probes in primary spinal astrocytes;
(ii) following this approach, we provide evidence of altered Ca2+ homeostasis in different domains of SOD1(G93A) astrocytes following SOCE or exposure to ATP;
(iii) in the attempt to mechanistically explain the observed Ca2+ phenomenology, we have undertaken (by classical biochemical and immunocytochemical approaches) a thorough comparative analysis of the expression of major Ca2+-transporting systems and other Ca2+related parameters in SOD1(G93A).
In conclusion our data emphasize that the expression of SOD1(G93A) is strictly correlated to altered Ca2+ homeostasis in spinal cord astrocytes, thereby supporting the hypothesis that in ALS astrocytes convey deadly signals to MNs through Ca2+-dependent mechanisms.

Abstract (italiano)

La sclerosi laterale amiotrofica (SLA) è una malattia neurodegenerativa fatale caratterizzata dalla morte selettiva dei motoneuroni (MN). Il meccanismo principe a cui è dovuto il danno neuronale è sconosciuto e non esiste un trattamento efficace per la cura di questa terribile malattia. In molti casi la SLA si sviluppa in maniera sporadica mentre nel 10% dei casi presenta una caratteristica genetica. Circa il 20% di questi casi famigliari sono causati da una mutazione nel gene della superossido dismutasi 1 (SOD1). In particolare, topi transgenici (Tg) esprimenti la mutazione SOD1 (G93A), correlata alla SLA, sviluppano un fenotipo molto simile a quello umano. Recenti ricerche hanno constatato come la proteina SOD1 mutata sia in grado di alterare l’omeostasi del calcio nei motoneuroni e negli astrociti limitrofi, rendendo le cellule neuronali particolarmente vulnerabili all’attivazione di un insieme di meccanismi possibilmente tossici. Considerando un tale stato dell’arte il nostro obiettivo, in questo progetto, è quello di confrontare flussi locali dello ione Ca2+ in motoneuroni e astrociti primari derivanti dal midollo spinale di topi SOD1(G93A) e SOD1(WT).
A questo scopo applicheremo due differenti approcci:
1. analisi dei flussi locali di Ca2+ in motoneuroni primari:
i) abbiamo ottimizzate le condizioni di estrazione e messa in coltura di motoneuroni primari dal midollo spinale di topi Tg;
ii) abbiamo ingegnerizzato e prodotto vettori virali adeno associati (AAV) per l’espressione delle sonde Ca2+ cameleon indirizzate a differenti compartimenti cellulari e sotto il controllo di un promotore motoneurone-specifico (derivato Hb9);
iii) abbiamo testato funzionalmente e usato con successo le sonde per la misurazione delle variazioni di Ca2+ in MN spinali primari, dimostrando una espressione specifica della sonda nei MN e un alterato (incrementato) ingresso di Ca2+ nel citosol dopo stimolazione con AMPA nei MN SOD1(G93A) messi a confronto con il controllo. Abbiamo inoltre dimostrato che queste sonde possono essere espresse in vivo in MN del midollo spinale attraverso una somministrazione sistemica a topi neonati.
2. Analisi dei flussi locali di Ca2+ e dei relativi parametri in astrociti spinali primari
Considerando il noto effetto di cross-talk degli astrociti sui motoneuroni nel progredire della malattia in topi con fenotipo SLA, abbiamo intrapreso una analisi comparativa dei flussi locali di Ca2+ in astrociti spinali primari derivanti da topi SOD1(G93A) e SOD1(WT).
Al fine di determinare se la mutazione G93A fosse in grado di causare una variazione dell’omeostasi del Ca2+ si è proceduto nel seguente modo:
i) inizialmente abbiamo settato le condizione per l’espressione in astrociti spinali primari di sonde Ca2+ indirizzate a specifici compartimenti cellulari;
(ii) successivamente ci siamo focalizzati sulle misure di calcio fornendo la prova della presenza di flussi alterati di calcio in differenti domini cellulari di astrociti SOD1(G93A) dopo stimolazione del SOCE o recettori purinergici;
(iii) nel tentativo di ipotizzare un possibile pathway che spiegasse la fenomenologia osservata abbiamo intrapreso una analisi comparativa (attraverso tecniche classiche di biochimica e immunocitochimica), in astrociti spinali primari SOD1(WT) e SOD1(G93A), dell’espressione dei principali sistemi di trasporto dello ione Ca2+ e di altri parametri correlati.
Concludendo i nostri dati enfatizzano che l’espressione di SOD1(G93A) è strettamente correlata con una omeostasi alterata dello ione Ca2+ in astrociti derivanti da midollo spinale, tutto ciò avvalora ulteriormente l’ipotesi di un cross-talk letale tra astrociti e motoneuroni attraverso un meccanismo Ca2+ dipendente.

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Tipo di EPrint:Tesi di dottorato
Relatore:Bertoli, Alessandro
Dottorato (corsi e scuole):Ciclo 29 > Corsi 29 > BIOSCIENZE E BIOTECNOLOGIE
Data di deposito della tesi:31 Gennaio 2017
Anno di Pubblicazione:31 Gennaio 2017
Parole chiave (italiano / inglese):amyotrophic lateral sclerosis neurodegenerative disease superoxide dismutase 1 Ca2+ homeostasis motor neurons MN-specific (Hb9-derived) promoter spinal astrocytes
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Area 06 - Scienze mediche > MED/04 Patologia generale
Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Centri > Centro Interdipartimentale di servizi A. Vallisneri
Dipartimenti > Dipartimento di Biologia
Codice ID:10206
Depositato il:16 Nov 2017 10:47
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