Disrupted Nuclear Protein Trafficking in Frontotemporal Dementia

Project Summary

Frontotemporal dementia shows considerable overlap at the molecular level with amyotrophic lateral sclerosis (ALS). Among their shared factors is a gene variant associated with a dysfunctional protein in the nerve cell nucleus. Usually, the nucleus carefully monitors traffic entering and exiting through its pores, which is key to healthy function of the cell. In its mutant form, the variant protein is associated with dysfunction in the nucleus surveillance system that leads to a host of snowballing downstream effects. One of these effects is buildup of a protein, TDP-43, that is implicated in frontotemporal dementia, ALS, and Alzheimer's disease.

Expanding on these findings, Alyssa Coyne, PhD, and her co-workers will use the gene-editing tool CRISPR to induce cells from adult donors to return to a stem cell state, before culturing them into genetically altered neurons. Using super-resolution imaging that gives a direct window onto molecules engaged in nuclear surveillance, the researchers will follow the steps from failed surveillance to cell injury. By homing in on this role of the nucleus, Dr. Coyne and her colleagues expect to uncover essential and novel insights into what leads to cell harm, highlighting potential therapeutic targets to prevent this injury.