1. Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation
- Author
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Park, Goonho, Xu, Ke, Chea, Leon, Kim, Kyle, Safarta, Lance, Song, Keon-Hyoung, Wu, Jian, Park, Soyoung, Min, Hyejung, Hiramatsu, Nobuhiko, Han, Jaeseok, and Lin, Jonathan H
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Neurodegenerative ,Alzheimer's Disease ,Acquired Cognitive Impairment ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Genetics ,Alzheimer's Disease Related Dementias (ADRD) ,Prevention ,Neurosciences ,Frontotemporal Dementia (FTD) ,Aging ,Dementia ,Brain Disorders ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Humans ,Disease Susceptibility ,eIF-2 Kinase ,Mutation ,Protein Aggregates ,Protein Aggregation ,Pathological ,Risk Factors ,tau Proteins ,Tauopathies ,EIF2AK3 ,ER stress ,PERK ,eIF2α phosphorylation ,integrated stress response ,neurodegeneration ,tau aggregation ,tauopathy ,unfolded protein response ,Chemical Sciences ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biological sciences ,Biomedical and clinical sciences ,Chemical sciences - Abstract
Tauopathies are neurodegenerative diseases caused by pathologic misfolded tau protein aggregation in the nervous system. 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. PERK is a key regulator of intracellular proteostatic mechanisms-unfolded protein response and integrated stress response. Previous studies found that tauopathy-associated PERK variants encoded functional hypomorphs with reduced signaling in vitro. But, it remained unclear how altered PERK activity led to tauopathy. Here, we chemically or genetically modulated PERK signaling in cell culture models of tau aggregation and found that PERK pathway activation prevented tau aggregation, whereas inhibition exacerbated tau aggregation. In primary tauopathy patient brain tissues, we found that reduced PERK signaling correlated with increased tau neuropathology. We found that tauopathy-associated PERK variants targeted the endoplasmic reticulum luminal domain; and two of these variants damaged hydrogen bond formation. Our studies support that PERK activity protects against tau aggregation and pathology. This may explain why people carrying hypomorphic PERK variants have increased risk for developing tauopathies. Finally, our studies identify small-molecule augmentation of PERK signaling as an attractive therapeutic strategy to treat tauopathies by preventing tau pathology.
- Published
- 2023