The American journal of pathology Lee, E., Diaz-Aguilar, M. Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients.Finally, our studies identify small molecule augmentation of PERK signaling as an attractive therapeutic strategy to treat tauopathies by preventing tau pathology. This may explain why people carrying hypomorphic PERK variants have increased risk for developing tauopathies. Our studies support that PERK activity protects against tau aggregation and pathology. ![]() We found that tauopathy-associated PERK variants targeted the ER luminal domain and two of these variants damaged hydrogen bond formation. In primary tauopathy patient brain tissues, we found that reduced PERK signaling correlated with increased tau neuropathology. Here, we chemically or genetically modulated PERK signaling in cell culture models of tau aggregation and found that PERK pathway activation prevented tau aggregation while inhibition exacerbated tau aggregation. But, it remained unclear how altered PERK activity led to tauopathy. Previous studies found that tauopathy-associated PERK variants encoded functional hypomorphs with reduced signaling in vitro. PERK is a key regulator of intracellular proteostatic mechanisms - Unfolded Protein Response (UPR) and Integrated Stress Response (ISR). Population studies implicate EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3), better known as PERK (protein kinase R-like endoplasmic reticulum kinase), as a genetic risk factor in several tauopathies. Tauopathies are neurodegenerative diseases caused by pathologic misfolded tau protein aggregation in the nervous system.
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