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Study uncovers a mechanism driving cognitive symptoms in Huntington's disease

March 06, 2017

Individuals affected by Huntington's disease (HD) inherit a mutation in the Huntingtin gene (HTT) that causes the encoded HTT protein to misfold and accumulate in neurons. This accumulation causes motor neuron degeneration, leading to the motor symptoms of the disease, including tremor and loss of muscle coordination. However, less is known about how the mutant HTT protein contributes to cognitive and psychiatric symptoms of HD. Researchers in Akira Sawa's lab at Johns Hopkins University investigated how HTT interacts with DISC1, a protein that is thought to be involved in schizophrenia and other mental illnesses. In a study published this week in the JCI, they used a mouse model that expresses the human HTT mutation (HD mice) and found that mutant HTT protein and DISC1 associate with each other to form a protein complex. DISC1's involvement in this complex compromises its other functions, leading to disruptions in downstream pathways. The researchers then developed a modified version of DISC1 that was unable to interact with the mutant HTT protein. Expression of the modified DISC1 normalized the activity of downstream pathways, which was associated with improvements in cognitive symptoms in the HD mice. These findings link abnormal DISC1 activity to HD-associated neuropsychiatric symptoms and provide further insights into DISC1's role in mental illness.
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TITLE: Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington's disease

AUTHOR CONTACT:

Akira Sawa
Johns Hopkins University School of Medicine
asawa1@jhmi.edu

View this article at:http://www.jci.org/articles/view/85594?key=eec4dc0612469d1ebebf

JCI Journals

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