Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome (in mice)

rvallee · Nov 15, 2019

In Down Syndrome Mouse Model, Scientists Reverse Intellectual Deficits with Drugs

In a surprising finding using the standard animal model of Down syndrome (DS), scientists were able to correct the learning and memory deficits associated with the condition — the leading genetic cause of cognitive disability and the most frequently diagnosed chromosomal disorder in the U.S. — with drugs that target the body’s response to cellular stresses.

Although the cognitive features of DS have generally been thought of as irreversible, the researchers say, these findings indicate that it may be possible to improve cognitive function in human DS using similar compounds.
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Abstract:

Down syndrome (DS) is the most common genetic cause of intellectual disability. Protein homeostasis is essential for normal brain function, but little is known about its role in DS pathophysiology. In this study, we found that the integrated stress response (ISR)—a signaling network that maintains proteostasis—was activated in the brains of DS mice and individuals with DS, reprogramming translation. Genetic and pharmacological suppression of the ISR, by inhibiting the ISR-inducing double-stranded RNA–activated protein kinase or boosting the function of the eukaryotic translation initiation factor eIF2-eIF2B complex, reversed the changes in translation and inhibitory synaptic transmission and rescued the synaptic plasticity and long-term memory deficits in DS mice. Thus, the ISR plays a crucial role in DS, which suggests that tuning of the ISR may provide a promising therapeutic intervention.
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https://science.sciencemag.org/content/366/6467/843

Hard to say whether this has any potential value to ME but cellular stress response is an area of research of great interest.

Hutan · Nov 15, 2019

It looks like double-stranded RNA-activated protein kinase is also referred to as PKR
Eiren Sweetman, the Otago University researcher, did her PhD on PKR in people with ME/CFS. It's discussed here.

Hutan said: ↑

They say that PKR has been called the 'universal immunological abnormality' in ME/CFS in this referenced paper (from 2008 - shouldn't something so universally abnormal have been shouted about more? )
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People with ME in their sample were more likely to have a higher level of activated PKR in their peripheral blood mononuclear cells than the healthy controls.

Will be interesting to see the paper behind this article.

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Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome (in mice)

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Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome (in mice)

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Hutan Moderator Staff Member

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