Alpha-Synuclein
Financiado
Blocking the prion like disease propagation in Parkinson s disease and related d...
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.
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...
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.
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Duración del proyecto: 42 meses
Fecha Inicio: 2018-02-26
Fecha Fin: 2021-08-31
Fecha Fin: 2021-08-31
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2021-08-31
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
MSCA-IF-2017:
Individual Fellowships
Cerrada
hace 7 años
Presupuesto
El presupuesto total del proyecto asciende a
200K€
Líder del proyecto
AARHUS UNIVERSITET
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
309.90K€ |
Participante