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.
‘Abnormal DISC1 activity has been linked to the neuropsychiatric symptoms associated with Huntington's disease.’
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.