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Berti, Giulia (2017) Exosomes as a vehicle for alpha-Synuclein toxic species propagation in alpha±-synucleinopathies. [Ph.D. thesis]

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Abstract (english)

alpha-synucleinopathies are a group of neurodegenerative disorders characterized by the presence of abnormally aggregated alpha-synuclein (aS). Recent evidence suggests that the early site of aS aggregation is synapses, where aS seems to play its physiological role. Moreover, aggregated aS is reported to be secreted by cells, suggesting its potential involvement in disease initiation and progression. Considering the nature of neurodegenerative disorders as well as the defined, step-wise spreading of Lewy body pathology in alpha-synucleinopathies, the idea of extracellular aS as a pathogenic prion-like agent is extremely appealing. This research project developed in this frame and it is focused on the propagation of aS toxic species mediated by a particular type of extracellular vesicles, exosomes. To this aim, exosomes containing aS and DOPAL modified aS oligomers were purified by HEK293T cells and we focused on the effect of these vesicles on different cell types. Since, in neurons, exosomes appear to be secreted in a spatially and regulated manner through synapses, we first investigate their effect on primary neuronal culture synapses . Upon incubation, aS containing exosomes and, more significantly, DOPAL-modified aS containing exosomes are delivered to synapses, where they alter proteins amounts, function and neuronal morphology. aS containing exosomes contribute also to neuroinflammation: they mediate increment of IL-1beta cytokine production in mouse immortalized microglia cells. Our results highlight an exosomes-driven toxicity of aS not only to neuronal synapses, but also to microglia, inducing the secretion of IL-1beta. Therefore, aS containing exosomes appear as a vehicle of aS toxicity, which might be interesting not only as a future therapeutic target, but also as a potential biomarker for alpha-synucleinopathies.

Abstract (italian)

Le alpha-sinucleinopatie sono un gruppo di malattie neurodegenerative caratterizzate dall'anormale aggregazione della proteina alpha-Sinucleina (aS). La localizzazione dell'aS è prevalentemente pre-sinaptica, ove sembra non solo svolgere la propria funzione fisiologica, ma anche iniziare l'alterazione patologica della sua struttura. Nonostante i meccanismi alla base di questo evento non siano noti, una delle ipotesi proposte è l'internalizzazione di specie tossiche di aS rilasciate da altre cellule. Queste forme di aS, infatti, al pari di quello che avviene nelle malattie prioniche, indurrebbero l'aggregazione dell'aS endogena. Tali premesse hanno indotto uno studio principalmente focalizzato sull'impatto a livello sinaptico di specie tossiche di aS veicolate dagli esosomi.
Gli esosomi sono stati purificati da cellule HEK293T trasfettate con aS-EGFP e trattate o meno con il DOPAL, un metabolita tossico della dopamina che è in grado di indurre l'aggregazione dell'aS. Una volta verificato che le vescicole contenessero specie aggregate di aS, queste sono state poi incubate con culture neuronali primarie. Per valutare il loro effetto a livello sinaptico sono stati presi in considerazione vari fattori. Per primo è stata dimostrata una riduzione dei livelli di sinaptofisina e PSD-95, due proteine marker rispettivamente della pre- e della post-sinapsi. Queste alterazioni sono anche accompagnate da una disfunzione a livello sinaptico, caratterizzata non solo da una diminuzione del numero di vescicole per sinapsi, ma anche da una loro maggiore distanza dalla zona attiva. Anche la morfologia neuronale è stata alterata mentre non si è registrato alcun aumento di marker necrotici o apoptotici.
Gli esosomi contenenti aS e aS modificata da DOPAL sono stati poi incubati con cellule di microglia primaria al fine di valutare se erano in grado di indurre una risposta infiammatoria. Il trattamento con gli esosomi ha aumentato la concentrazione della citochina pro-infiammatoria IL-1beta nel medium, facendo ipotizzare un loro coinvolgimento anche nella neuro-infiammazione. In conclusione questi dati suggeriscono che gli esosomi rilasciati dalle cellule e contenenti specie aggregate di aS propaghino la tossicità  a livello neuronale e stimolino nella microglia la produzione di fattori pro-infiammatori, creando una sorta di circolo vizioso che ne aumenta l'effetto patologico. Gli esosomi contenenti specie aggregate di aS potrebbero quindi non solo diventare nuovi target terapeutici, ma anche potenziali biomarker per la diagnosi delle alfa-sinucleinopatie.

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EPrint type:Ph.D. thesis
Tutor:Bubacco, Luigi
Supervisor:Papini, Emanuele
Ph.D. course:Ciclo 29 > Corsi 29 > BIOSCIENZE E BIOTECNOLOGIE
Data di deposito della tesi:31 January 2017
Anno di Pubblicazione:31 January 2017
Key Words:alfa-sinucleina/alpha-synuclein esosomi/exosomes sinapsi/synapses
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/09 Fisiologia
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:10012
Depositato il:14 Nov 2017 11:52
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