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 | Projekt | Informationsblatt | H2020 | CORDIS

Projektbeschreibung

Die prionenähnliche Natur der Parkinson-Krankheit entschlüsseln: ein Paradigmenwechsel

Die unkontrollierbaren Bewegungen, die mit der Parkinson-Krankheit einhergehen, sind das Ergebnis einer chronischen neuronalen Degeneration. Eines der Kennzeichen der Pathophysiologie der Parkinson-Krankheit ist die Ansammlung von Aggregaten des Proteins α-Synuclein. Im Rahmen des über die Marie-Skłodowska-Curie-Maßnahmen finanzierten Projekts Alpha-Synuclein wird von der Hypothese ausgegangen, dass sich α-Synuclein wie ein Prion verhält und sich vom peripheren auf das zentrale Nervensystem ausbreitet, wodurch sich der oxidative Stress und die Funktionsstörung verstärken und ein Verlust von Neuronen im Gehirn stattfindet. Um diese Neurotoxizität und Degeneration zu verhindern, schlagen die Forschenden vor, ein neues Modell zur Untersuchung der Ausbreitung von α-Synuclein zu schaffen, das sich auf die Rolle bestimmter Gene bei der Ausbreitung und Toxizität von α-Synuclein konzentriert.

Ziel

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.