Parkinson's disease is characterized by α-synuclein aggregation and loss of dopaminergic neurons. The risk of developing the disease is due to a combination and interaction of genetic and environmental factors. Thanks to previous studies, the inverse association between smoking and risk of developing Parkinson's disease is well known, as well as evidence that at the genetic level it could be synaptic vesicle glycoprotein 2 that is the important mediator of this inverse correlation. The aim of the studies performed is therefore to try to determine the mechanism of smoke-SV2C interaction in a D. melanogaster model of Parkinson's disease. Specifically, to do this, a model was used that expressed α-synuclein in all neurons, leading to the development of the hallmarks of the disease, including motor dysfunction, loss of dopaminergic neurons, and formation of α-synuclein inclusions. Therefore, the effect of treating such models with increasing doses of nicotine with respect to the previously mentioned parameters was evaluated in the presence or absence of knockdown of the two orthologs of SV2 in D. melanogaster. From the data obtained from these studies, it is possible to confirm the gene-environment interaction between nicotine and SV2, defining a key role of this interaction in α-synuclein proteostasis, and thus paving the way for future clinical studies exploiting the neuroprotective effect of nicotine. In addition, this study provides evidence that the exploited model can be used for the study of further gene-environment interactions.
La malattia di Parkinson è caratterizzata dall'aggregazione di α-sinucleina e dalla perdita di neuroni dopaminergici. Il rischio di sviluppare la malattia è dovuto a una combinazione e interazione di fattori genetici e ambientali. Grazie a studi precedenti è ben nota l'associazione inversa tra fumo e rischio di sviluppare la malattia di Parkinson, così come si è evidenziato che a livello genetico potrebbe essere la glicoproteina 2 della vescicola sinaptica l’importante mediatore di questa correlazione inversa. L’obiettivo degli studi effettuati è quindi quello di cercare di determinare il meccanismo di interazione fumo-SV2C in un modello di D. melanogaster della malattia di Parkinson. In particolare, per fare ciò, è stato utilizzato un modello che esprimesse α-sinucleina in tutti i neuroni, portando allo svilupparsi dei tratti distintivi della malattia, tra cui disfunzione motoria, perdita di neuroni dopaminergici e formazione di inclusioni di α-sinucleina. Si è dunque valutato l’effetto del trattamento di tali modelli con dosi crescenti di nicotina rispetto ai parametri prima citati, in presenza o in assenza di knock down dei due ortologhi di SV2 in D. melanogaster. Dai dati ottenuti da questi studi è possibile confermare l’interazione gene-ambiente tra nicotina e SV2, definendo un ruolo chiave di questa interazione nella proteostasi dell'α-sinucleina, e aprendo così la strada a futuri studi clinici che sfruttino l’effetto neuroprotettivo della nicotina. Inoltre, questo studio fornisce una prova che il modello sfruttato può essere utilizzato per lo studio di ulteriori interazioni gene-ambiente.
La protezione dalla tossicità dell’α-sinucleina, mediata dalla nicotina, richiede la presenza della proteina SV2 in Drosophila melanogaster
COSCI, CHIARA
2022/2023
Abstract
Parkinson's disease is characterized by α-synuclein aggregation and loss of dopaminergic neurons. The risk of developing the disease is due to a combination and interaction of genetic and environmental factors. Thanks to previous studies, the inverse association between smoking and risk of developing Parkinson's disease is well known, as well as evidence that at the genetic level it could be synaptic vesicle glycoprotein 2 that is the important mediator of this inverse correlation. The aim of the studies performed is therefore to try to determine the mechanism of smoke-SV2C interaction in a D. melanogaster model of Parkinson's disease. Specifically, to do this, a model was used that expressed α-synuclein in all neurons, leading to the development of the hallmarks of the disease, including motor dysfunction, loss of dopaminergic neurons, and formation of α-synuclein inclusions. Therefore, the effect of treating such models with increasing doses of nicotine with respect to the previously mentioned parameters was evaluated in the presence or absence of knockdown of the two orthologs of SV2 in D. melanogaster. From the data obtained from these studies, it is possible to confirm the gene-environment interaction between nicotine and SV2, defining a key role of this interaction in α-synuclein proteostasis, and thus paving the way for future clinical studies exploiting the neuroprotective effect of nicotine. In addition, this study provides evidence that the exploited model can be used for the study of further gene-environment interactions.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/51919