Stereoselective methyl-swapping demonstrates target specificity of cognitive enhancer
Boone, M.; Dalwadi, U.; Deal, A.; Zhu, P. J.; Croll, T. I.; Yamazaki, M.; Prescott, K.; Minopoli, R.; Biscocho, I.; Wang, J.; Lee, D. J.; Arthur, C. P.; Laughlin, T. G.; Zhou, H.; Klope, M. T.; Egea, P. F.; Schoof, M.; Lawrence, R.; Renslo, A. R.; Costa-Mattioli, M.; Frost, A.; Walter, P.
Show abstract
The Integrated Stress Response (ISR) couples cellular stress sensing to translational control, playing a critical role in the homeostatic regulation of cell health. However, prolonged and unmitigated ISR activation becomes maladaptive and drives the progression of a wide range of pathologies, including cognitive decline. Pharmacological inhibition of the ISR with the small, drug-like molecule ISRIB has proven remarkably effective in reversing cognitive deficits and pathology in animal models, highlighting its potential for therapeutic intervention in humans. We engineered an allele-specific ISRIB analog (mISRIB) that selectively targets a mutant form of eIF2B, the molecular target of ISRIB, without affecting wild-type eIF2B. Notably, mISRIB treatment in mice homozygous for the eIF2B mutant allele enhances synaptic plasticity and long-term memory, confirming the on-target mechanism underlying ISRIBs cognitive benefits. Our results provide a framework for dissecting the ISRs contributions within complex cellular networks, such as those governing brain function, with precise temporal and spatial resolution.
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