Modeling gene-environment interactions in Parkinson’s Disease:Helicobacter pyloriinfection ofPink1−/−mice induces CD8 T cell-dependent motor and cognitive dysfunction

Author:

Kazanova AlexandraORCID,Sung JacquelineORCID,Oliveira Nathalia,Gavino ChristinaORCID,Recinto SherilynORCID,Bessaiah HichamORCID,Pei JessicaORCID,Burns LindsayORCID,Miller Willemein,Brouillard-Galipeau MorganeORCID,Zhu Lei,Guerra Lucia,Elemeery Moustafa NouhORCID,MacDonald AdamORCID,Lanoix Joel,Thibault PierreORCID,McBride Heidi,Desjardins MichelORCID,Stratton Jo AnneORCID,Labrecque Nathalie,Gruenheid SamanthaORCID

Abstract

AbstractParkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of motor function. Diagnosis occurs late: after motor symptom development downstream of the irreparable loss of a large proportion of the dopaminergic neurons in thesubstantia nigraof the brain. Understanding PD pathophysiology in its pre-motor prodromal phase is needed for earlier diagnosis and intervention. Genetic risk factors, environmental triggers, and dysregulated immunity have all been implicated in PD development. Here, we demonstrate in a mouse model deficient in the PD-associated genePink, that infection with the human PD-associated gastric bacteriumHelicobacter pylorileads to development of motor and cognitive signs resembling prodromal features of PD. This was also associated with proliferation and activation of primary mitochondria-reactive CD8 T cells and infiltration of CD8 T cells into the brain. Development of the motor and cognitive phenotypes in the infectedPink1−/−mice was abrogated when CD8 T cells were depleted prior to infection. We anticipate that this new model, which integrates genetic PD susceptibility, a PD-relevant environmental trigger, and specific immune changes that are required for symptom development, will be a valuable tool for increasing our understanding of this complex disease.

Publisher

Cold Spring Harbor Laboratory

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