La propagation de la protéine alpha-synucléine dans la maladie de Parkinson : étude dans les organoïds mésencéphaliques dérivés de patients

 

NGUYEN-VI MOHAMED

Université McGill

 

Domaine : neurosciences, santé mentale et toxicomanies

Programme Formation postdoctorale (CITOYENS CANADIENS ET RÉSIDENTS PERMANENTS)

Concours 2018-2019

Partenaire :

Société Parkinson du Canada

The first gene to be linked to Parkinson's disease (PD) was SNCA, which encodes the protein alpha-synuclein (α-syn). PD is also characterized by the progressive loss of dopaminergic neurons in the substancia nigra of the midbrain, accompanied by the presence of α-syn proteins aggregates, demonstrated to spread throughout the brain as the disease progresses. The regions affected are interconnected implying that α-syn is being propagated between neurons. Thus, developing new therapies focused on impeding this process represents a novel therapeutic avenue that merits exploration. Most studies have investigated the propagation of α-syn in 2D cell cultures and mouse models. While the cell cultures are informative, they lack the interconnectedness of brain, in which neurons form extensive 3D network. Often promising therapies developed in mouse models fail due to intrinsic differences that exist between mice and humans. Advances in human stem cell technology now made physiological 3D human models feasible, with induced pluripotent stem cells that can generate an interconnected 3D human neuronal network, similar in architecture and composition to the human brain.

The global aim of my research is to build upon existing 2D cell cultures and mouse models by investigating the process of α-syn propagation in a 3D human model « midbrain minibrains » of Parkinson's disease patients carrying SNCA triplication and controls. To achieve this, I will investigate the propagation of α-syn within this 3D human synaptic network to elucidate the pathway through which these aggregates move between neurons. After the identifications of the pathological mecanisms involved, i will perform a drug screening compounds to decrease the propagation of PD. My research will provide new insights on the propagation of α-syn in an innovative human system connected and thereby will have direct impact on the development of novel therapeutic interventions to block the progression of PD.