Science: activation of ISR switch is expected to treat Down's syndrome

November 19, 2019 / Biovalley BIOON / -- Down syndrome is the most common genetic cause of mental disorders, and there is no effective treatment at present Memory impairment is a typical feature of this disease In a new study, researchers from Baylor Medical College and other research institutions reported that a defect in the conservative stress pathway called integrated stress response (ISR) may explain the cognitive defect in Down's syndrome mouse model The relevant research results were published in the Science Journal on November 15, 2019, and the title of the paper is "activation of the ISR medites the behavioral and neurological abnormalities in Down syndrome" The authors found that ISR was activated in the brains of mice that reproduced cognitive impairment in patients with Down's syndrome, and also in human brain samples after death What's more, whether it is through genetic means or drug means to inhibit ISR, these mice can reverse the memory deficit These findings support future studies to explore whether regulation of ISR may contribute to the treatment of Down's syndrome and other diseases caused by disruption of the ISR pathway "In the current study, we have studied the role of protein homeostasis network in Down's syndrome," said Dr Mauro Costa Mattioli, co-author and professor of Neuroscience at Baylor College of medicine The decline of protein homeostasis network is closely related to a variety of nervous system diseases (from aging to neurodegenerative diseases), but little is known about its role in Down's syndrome " The researchers first found that protein synthesis in the brains of Down's syndrome mice and in human cells isolated from people with the syndrome decreased They also found that activation of ISR, an evolutionary network that regulates protein homeostasis by regulating protein synthesis, could account for protein synthesis defects associated with Down's syndrome Inspired by these encouraging findings, Costa Mattioli and his colleagues studied whether activation of ISR mediates long-term memory deficits in Down's syndrome mice To solve this problem, they used four independent genetic and drug manipulation methods to correct ISR in Down's syndrome mouse model Dr Ping Jun Zhu, lead author of the paper and senior researcher of Costa Mattioli team, said, "mice with Down's syndrome show long-term memory problems In a group of experiments, we conducted a new task training for Down's syndrome mice and control mice The learning ability of Down syndrome mice was lower than that of control mice However, when we inhibit ISR by genetic means or drugs, these mice learn almost as well as the control mice " The researchers also measured the strength of synaptic connections in Down's syndrome mice and found that their synaptic connections were not as strong as those in the control mice But inhibition of ISR in Down's syndrome mice can reverse synaptic dysfunction At the cellular level, synaptic plasticity - the ability to form neural connections - is thought to be a key mechanism for explaining the way memory is formed, so these findings support the hypothesis put forward by these researchers that activation of the ISR network mediates memory deficits associated with Down's syndrome "Over the past decade, we and others have shown that ISR is a normal molecular switch for long-term memory formation," Costa Mattioli said In this study, we found that this switch is off in Down's syndrome More importantly, turning the switch back on can reverse their memory defects These encouraging results suggest that the adjustment of ISR may be a promising way to alleviate a series of cognitive disorders caused by the disturbance of protein homeostasis " (BIOON Com) reference: 1 Ping Jun Zhu et al Activation of the ISR medites the behavioral and neurobiological abnormalities in Down syndrome Science, 2019, DOI: 10.1126/science.aaw5185 2 Mark Halliday et al Translating translation in Down syndrome Science, 2019, doi:10.1126/science.aaz7128 3.Restoring protein homeostasis improves memory deficits in Down syndrome model https://medicalxpress.com/news/2019-11-protein-homeostasis-memory-deficits-syndrome.html