A new research conducted at The Picower Institute for Learning and Memory at MIT finds that the protein CPG2 is significantly less abundant in the brains of people with bipolar disorder (BD). The study further finds how specific mutations in the SYNE1 gene that encodes the protein undermine its expression and its function in neurons.
The study, led by Elly Nedivi, professor in MIT's departments of Biology and Brain and Cognitive Sciences, and former postdoc Mette Rathje shows how a set of genetic differences in patients with BD can lead to specify physiological dysfunction for neural circuit connections or synapses in the brain.
Speaking about the study, Nedivi said that the mechanistic detail and specificity of the findings provide new and potentially important information for developing novel treatment strategies and for improving diagnostics.
The researcher said, "It's a rare situation where people have been able to link mutations genetically associated with increased risk of a mental health disorder to the underlying cellular dysfunction," adding, "For bipolar disorder this might be the one and only."
Notably, the researchers are not suggesting that CPG2-related variations in SYNE1 are "the cause" of bipolar disorder, but rather that they likely contribute significantly to susceptibility to the disease.
Experts found that sometimes combinations of the variants, rather than single genetic differences, were required for significant dysfunction to become apparent in laboratory models.
"Our data fit a genetic architecture of BD, likely involving clusters of both regulatory and protein-coding variants, whose combined contribution to phenotype is an important piece of a puzzle containing other risk and protective factors influencing BD susceptibility," the authors wrote.
The findings show how genetic variations associated with BD disrupt the levels and function of a protein crucial to synaptic activity and therefore the health of neural connections. It remains to be shown how these cellular deficits manifest as bipolar disorder.
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