Blocking the prion-like disease propagation in Parkinson’s disease and related disorders – model development and identification of cell-autonomous and cell non-autonomous factors. | Alpha-Synuclein | Progetto | Scheda informativa | H2020 | CORDIS

Descrizione del progetto

Svelare la natura prionica del morbo di Parkinson: un cambiamento di paradigma

Il movimento incontrollabile associato al morbo di Parkinson è il risultato di una degenerazione neurale cronica. Uno dei tratti distintivi della fisiopatologia di questa patologia è l’accumulo di aggregati della proteina alfa-sinucleina. Il progetto Alpha-Synuclein, finanziato dal programma di azioni Marie Skłodowska-Curie, si basa sull’ipotesi che l’alfa-sinucleina si comporti come un prione, diffondendosi dal sistema nervoso periferico al sistema nervoso centrale, esacerbando lo stress ossidativo e la disfunzione e portando alla perdita di neuroni nel cervello. Per prevenire questa neurotossicità e degenerazione, i ricercatori suggeriscono di creare un nuovo modello per studiare la propagazione dell’alfa-sinucleina, concentrandosi sul ruolo di geni specifici nella sua tossicità e diffusione.

Obiettivo

A prion-like behavior of α-synuclein (AS) protein has been hypothesized in the pathogenesis of Parkinson disease (PD). According to this hypothesis, pathogenic forms “seeds” of AS propagate from periphery into the neurons of central nervous system (CNS), where they recruit endogenous AS in the first receiving neurons, exit the cell and enter connected neurons. The ongoing AS aggregation and cell-cell propagation is considered to induce oxidative stress, neuronal dysfunction and neuronal loss in CNS. Therefore, blocking the neuronal propagation of AS will prevent AS neurotoxicity and neurodegeneration. I propose to develop and validate a novel in vivo model of prion-like AS propagation, in which I will selectively modify the genetic makeup of first receiving neurons, and use this model for mechanistic investigations. I will use a transgenic M83 mouse model overexpressing mutant A53T human AS in which prion-like spreading is initiated by injecting preformed AS aggregates into the hindlimb musculus femoris. These AS aggregates are taken up by sensory and/or motor nerve endings in the muscle, are retrogradely transported through the sciatic nerve into spinal cord, and rostrally into the brainstem and higher brain areas over time. I will refine this model by transducing the sciatic nerve endings with intramuscular delivery of rAAV viral vectors- containing novel CRISPR/Cas9 genome editing tools targeting genes of interest- to prevent in vivo prion-like AS spreading and/or toxicity. As proof of concept, I will silence AS in the receiving neurons to demonstrate this slows the disease development in the model. Once validated, I will use the model for hypothesis-driven mechanistic investigations of candidate genes, which initially include: 1) ubiquitin specific peptidase 19 (USP19)- since it has been implicated in cellular excretion of misfolded AS in vitro, and 2) eukaryotic elongation factor-2 kinase (eEF2K)- since it is abnormally activated in postmortem PD brain tissue.