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Tauopathies and PERK

The ER stress sensor PERK (protein kinase R-like ER kinase) participates in the pathogenesis and progression of tauopathies. However, the mechanism by which the PERK pathway causes neuronal dysfunction is still unknown. These projects focus on investigating the PERK-tau relationship in aging, tauopathy, and injury.

PERK as a central mediator of tau biology in aging and disease.

The long-term goal of this project is to elucidate the pathway(s) that induce(s) neuronal dysfunction in tauopathies, and the overall objective is to determine the mechanism by which tau and PERK synergize to promote neuronal dysfunction. The central hypothesis is that tau and PERK engage in a pathological cycle whereby aberrant accumulation of tau chronically induces PERK to activate enzymes that contribute to the production of pathogenic tau. The overall consequence of this cycle is potentiation of pathogenic tau pathways as well as chronic inhibition of protein synthesis. Characterizing the role of the PERK pathway in neuronal dysfunction will identify novel and urgently needed therapeutic targets for tauopathies. 

The impact of PERK activity on brain function / dysfunction in health and head injury.

There is a critical and urgent need to improve the quality of life of individuals who suffer head injuries, especially since recent studies link TBI with increased risk for AD. Due to significant variability in the nature of injuries, such as severity and repetition, it is extremely challenging to determine the molecular mechanisms linking TBI and AD. This project is designed to address this challenge. 

PERK inhibition as a therapeutic strategy for Alzheimer disease

 

The overall objective of this proposal is to determine the impact of PERK inhibition on the UPR, tau pathology, brain structure, and synaptic integrity using manganese-enhanced (ME-MRI) in a tauopathic mouse model of Alzheimer’s disease (AD). Project 1 will determine the impact of PERK inhibition on tau pathology and UPR markers in rTg4510 mice. Project 2 will determine the effect of PERK inhibition on brain atrophy (volumetric T2 MRI) and synaptic integrity (ME-MRI) in rTg4510 mice.

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