Down syndrome (DS), a neurodevelopmental disorder that results from the presence of an extra copy of chromosome 21, is a common cause of intellectual disability in the general population, but little is known about the molecular mechanisms that underlie the cognitive deficits. In a new study published in Science, Mauro Costa-Mattioli, Peter Walter and colleagues provide evidence that a signalling network known as the integrated stress response (ISR) mediates cognitive decline in DS.

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“We hypothesized that loss of proteostasis — the process by which the cell’s proteins are monitored and maintained at homeostasis — could explain the memory deficits associated with DS,” comments Costa-Mattioli. “Protein synthesis is known to be required for long-term memory formation, and loss of proteostasis is associated with a wide range of cognitive and neurodegenerative disorders.”

The ISR is an evolutionarily conserved pathway, the normal role of which is to regulate protein synthesis under conditions of cellular stress. To investigate the relationship between the ISR and cognitive impairment in DS, Costa-Mattioli and colleagues used the Ts65Dn mouse model, which recapitulates the types of cognitive deficit that are observed in humans with this condition.

Activation of the ISR, as indicated by phosphorylation of eukaryotic translation initiation factor 2 (eIF2), was detected in the hippocampus in the Ts65Dn mice and also in post-mortem brain tissue samples from people with DS. ISR activation led to reductions in protein synthesis in the brains of Ts65Dn mice and in induced pluripotent stem cells derived from individuals with DS.

Genetic or pharmacological inhibition of the ISR was found to restore protein synthesis and improve long-term memory in Ts65Dn mice. “We have previously identified that the ISR serves as a long-term memory switch, and in this study we found that the switch is off in DS,” explains Costa-Mattioli. “We showed that turning the switch back on by inhibiting the ISR reverses the cognitive decline associated with DS.”

We have previously identified that the ISR serves as a long-term memory switch, and in this study we found that the switch is off in DS

The new findings raise the possibility that pharmacological manipulation of the ISR could help to alleviate cognitive impairments in individuals with DS. The investigators plan to further explore the mechanisms that lead to ISR activation in DS and to determine whether ISR inhibition can reverse cognitive deficits in other neurological conditions in which proteostasis is dysregulated.