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Rodella, Umberto (2017) A novel model of Miller Fisher syndrome to study motor axon terminal regeneration. [Ph.D. thesis]

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Abstract (english)

The neuromuscular junction (NMJ) is a ‘tripartite’ synapse, composed of the presynaptic motor axon terminal (MAT), the muscle fiber and perisynaptic Schwann cells (PSCs). NMJ functionality is essential for the execution of body movements and it is anatomically exposed, becoming an easy target of bacterial and animal neurotoxins, toxic chemicals, mechanical trauma, and autoimmune diseases.
In the Miller Fisher Syndrome (MFS) autoantibodies against specific gangliosides (>90% GQ1b) bind to MAT and in turn activate the complement system cascade at its surface, leading to nerve degeneration. Such damage is reversible, as the motor neuron is able to fully regenerate and restore neurotransmission.
PSCs are main supporters of NMJ regeneration: to date, however, the current understanding of PSCs role in this autoimmune neuropathy is mostly phenomenological, and molecular studies are needed. It was recently reported that the degenerating MAT release alarm signals (alarmins) able to activate the pro-regenerating phenotype of PSCs. Therefore, MAT can be considered an active player of its own regeneration. In addition, many other signals are thought to be generated by all the three main components of the NMJ, thus generating a complex inter-cellular communication network, which has been only partially identified.
In order to better elucidate the molecular and cellular events driving PSCs response to MAT damage in MFS, we recently developed a novel in vivo MFS model. The combination of FS3, a monoclonal antibody against gangliosides related to MFS, and normal human serum (NHS) as a source of complement, administered subcutaneously in LAL muscles and intramuscularly in soleus muscle in mice, causes the degeneration of MAT. Soon after MAT destruction, neuronal debris are engulfed and digested by PSCs. Within few days after injection MAT regrowth is morphologically and functionally complete, as assessed by immunofluorescence analysis and electrophysiological recordings. The effect is antibody- and complement-dependent, as no MAT degeneration takes place in the absence of FS3, nor when NHS is heat-inactivated.
To identify the neuronal alarmins responsible for PSCs activation and the signaling pathways engaged, we have parallely set up an in vitro MFS model consisting of administration of FS3 plus NHS to primary cerebellar neurons and spinal cord motor neurons, which causes a complement-dependent massive Ca2+ overload in neurite, together with the formation of neurite enlargements, named bulges. Bulges are sites of accumulation of swollen and dysfunctional mitochondria, and of localized hydrogen peroxide (H2O2) production. Hydrogen peroxide is an alarm signal for SCs. Indeed, in FS3 plus NHS attacked neurons-SCs co-cultures, neuron-derived H2O2 induces activation of the ERK1/2 pathway in SCs, a known crucial player of the switch toward a pro-regenerative phenotype of SCs.
In addition, we identified adenosine triphosphate (ATP) as an additional alarmin involved in SCs activation. Indeed, primary neurons exposed to FS3 plus NHS release ATP in the extracellular medium, which in turn evokes intracellular calcium spikes within SCs in co-cultures with neurons. These spikes were significantly abolished in the presence of the ATP-inactivating enzyme apyrase in the incubation medium.
Furthermore, experiments with a FRET-based cyclic AMP (cAMP) sensor show that, upon FS3 plus NHS addition in neurons-SCs co-cultures, cAMP levels rise in SCs, and this event eventually results in an ATP-dependent increased phosphorylation the transcription factor CREB (cAMP response element-binding protein).
In conclusion, the work performed during this PhD project has led to the development of novel in vitro and in vivo models of MFS, in order to study the molecular communication between MAT and PSCs. Hydrogen peroxide and ATP were found to be important neuronal alarmins, able to activate pro-regenerative pathways within SCs.
We believe these results throw light on the molecular and cellular events taking place in MFS, and may well be extended to other MAT affecting pathologies.

Abstract (italian)

La giunzione neuromuscolare (neuromuscular junction, NMJ) è una sinapsi ‘tripartita’, composta da un terminale assonico di un motoneurone (motor axon terminal, MAT), una fibra muscolare postsinaptica, e da cellule di Schwann perisinaptiche (perisynaptic Schwann cells, PSC). La funzionalità della NMJ è essenziale per l’esecuzione dei movimenti corporei. Tuttavia la sua anatomia la rende particolarmente esposta ad una vasta gamma di stimoli patologici, quali neurotossine animali e batteriche, sostanze tossiche, traumi meccanici e malattie autoimmuni.
Nella sindrome di Miller Fisher (Miller Fisher Syndrome, MFS), auto-anticorpi riconoscono specifici gangliosidi (>90% GQ1b) presenti nel MAT e attivano la cascata del complemento alla sua superficie, causandone la degenerazione. Questo danno è reversibile, in quanto il MAT è in grado di rigenerare completamente e di ristabilire la trasmissione sinaptica.
Le PSC sono tra i principali effettori della rigenerazione della NMJ. Ad oggi, tuttavia, l’attuale comprensione dei ruoli di queste cellule in questa neuropatia autoimmune è principalmente fenomenologica, e ulteriori studi molecolari.
È stato riportato che il MAT in degenerazione rilascia segnali di allarme (alarmine) capaci di attivare il fenotipo di pro-rigenerazione delle PSC. Dunque si può dedurre che il MAT gioca un ruolo attivo nel processo della propria degenerazione. Inoltre è probabile che molti altri segnali siano generati da parte di tutti e tre i componenti della NMJ, che generano così un network complesso di comunicazione intercellulare, il quale è stato solo parzialmente compreso.

Nel progetto di dottorato qui presentato è stato sviluppato un nuovo modello in vivo di MFS, allo scopo di chiarire gli eventi molecolari e cellulari che avvengono nelle PSC in seguito a danno del MAT osservato nella MFS. Ciò è stato permesso tramite l’utilizzo di FS3, un anticorpo monoclonale che riconosce gangliosidi associati alla MFS, e siero umano (normal human serum, NHS), utilizzato come fonte di proteine del complemento. La amministrazione subcutanea nel muscolo LAL, o intramuscolare nel muscolo soleo, della combinazione di questi due elementi induce la degenerazione del MAT, e i suoi frammenti vengono fagocitati e degradati dalle PSC. Entro pochi giorni dall’iniezione la rigenerazione del MAT è completa sia a livello morfologico che funzionale, come evidenziato da analisi di immunofluorescenza ed elettrofisiologiche. Gli effetti osservati sono strettamente dipendenti dall’anticorpo e dal sistema del complemento, in quanto non viene osservata neurodegenerazione in assenza di FS3 o quando il NHS viene inattivato al calore.

Allo scopo di identificare le alarmine neuronali responsabili dell’attivazione delle PSC e le conseguenti risposte molecolari di quest’ultime, è stato parallelamente sviluppato un modello in vitro di MFS, che consiste nell’esposizioneì della combinazione di FS3 e NHS (FS3+NHS) a colture primarie di neuroni cerebellari o di motoneuroni da midollo spinale. Ciò causa un’entrata massiccia e incontrollata di calcio (Ca2+) a livello dei neuriti, associata alla formazione di protuberanze, o bulges, a livello dei neuriti stessi. Questi bulges sono siti di accumulo di mitocondri gonfi e disfunzionali, e di produzione di perossido di idrogeno (H2O2). Il perossido di idrogeno è un segnale di allarme per le cellule di Schwann (Schwann cells, SC). Infatti in co-colture di neuroni e SC, il H2O2 derivante dai neuroni attaccati da FS3+NHS induce l’attivazione nelle SC del pathway di ERK1/2, conosciuto per il suo importante ruolo di induzione del fenotipo pro-rigenerazione delle SC.
Inoltre, tramite il modello in vitro di MFS, è stata identificata una seconda alarmina coinvolta nell’attivazione delle SC, l’adenosina trifosfato (ATP).
Infatti, neuroni primari esposti al complesso FS3+NHS rilasciano nel mezzo extracellulare ATP, che a sua volta induce oscillazioni intracellulari di Ca2+ nelle SC. Queste oscillazioni sono abolite in presenza di apirasi, un enzima che degrada l’ATP, nel mezzo di incubazione.
In aggiunta, esperimenti con un sensore FRET per l’AMP ciclico (cAMP) hanno mostrato che i livelli di SC aumentano in co-colture di neuroni e SC in seguito al danno neuronale esercitato da FS3+NHS. All’aumento di cAMP intracellulare osservata ne consegue un’aumentata fosforilazione (ovvero attivazione) del fattore di trascrizione CREB (cAMP response element-binding protein), anch’essa ATP-dipendente.

In conclusione, il lavoro svolto in questo progetto di dottorato ha portato allo sviluppo di nuovo modelli in vivo e in vitro di MFS. Questi sono stati utilizzati per lo studio della comunicazione molecolare tra il MAT e le PSC. Il perossido di idrogeno e l’ATP sono stati identificati come importanti alarmine neuronali, capaci di attivare il fenotipo pro-rigenerazione delle SC.
Crediamo che questi risultati contribuiscano a gettare luce sugli eventi molecolari e cellulari che avvengono alla NMJ nella MFS, e che queste conoscenze possano venire estese anche ad altre patologie che affliggono il MAT.

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EPrint type:Ph.D. thesis
Tutor:Montecucco, Cesare
Supervisor:Rigoni, Michela
Ph.D. course:Ciclo 29 > Corsi 29 > BIOSCIENZE E BIOTECNOLOGIE
Data di deposito della tesi:28 January 2017
Anno di Pubblicazione:28 January 2017
Key Words:ATP, calcium, cyclic AMP, phospho-CREB, Miller Fisher syndrome, Schwann cells, ERK1/2, Neuromuscular junction, Hydrogen peroxide / ATP, calcio, AMP ciclico, fosfo-CREB, sindorme di Miller Fisher, cellule di Schwann, ERK1/2, Giunzione Neuromuscolare, Perossido di Idrogeno
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:10020
Depositato il:24 Nov 2017 10:16
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