Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response

Area of Science:

• Cellular biology
• Neuroscience
• Genetics

Background:

• The integrated stress response (ISR) is crucial for maintaining cellular balance and cognitive abilities.
• Dysregulation of the ISR is implicated in various neurological disorders.

Purpose of the Study:

• To investigate the impact of persistent ISR activation on cognitive function using a mouse model.
• To explore the therapeutic potential of inhibiting the ISR.

Main Methods:

• Generated a mouse model with the PPP1R15B^R658C variant linked to intellectual disability.
• Analyzed the effects of ISR activation on protein synthesis and memory in mice.
• Characterized DP71L, a viral ISR inhibitor, and tested its efficacy in various disease models.

Main Results:

• The PPP1R15B^R658C variant caused persistent ISR activation, impaired protein synthesis, and long-term memory deficits.
• Cognitive and synaptic impairments were directly linked to ISR activation in the mouse model.
• DP71L effectively reversed cognitive and synaptic deficits in mouse models of Down syndrome, Alzheimer's disease, and aging.
• DP71L enhanced synaptic plasticity and memory in healthy mice.

Conclusions:

• Persistent ISR activation due to the PPP1R15B^R658C variant leads to cognitive impairment.
• DP71L, a viral ISR inhibitor, demonstrates broad therapeutic potential for cognitive and synaptic deficits across multiple conditions and in healthy individuals.