Disrupted Nuclear Protein Trafficking in Frontotemporal Dementia

In this project, researchers will focus on a genetically linked dementia to map the role of the nerve cell nucleus in cell injury.

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.

This proposal expands upon our recent work implicating the CHMP7-ESCRT-III nuclear surveillance pathway in the initiation of early and significant pathophysiological cascades impacting the NPC and ultimately contributing to TDP-43 dysfunction and mislocalization in sporadic ALS and C9orf72 FTD/ALS. Our new preliminary data suggest that abnormal CHMP7/ESCRT-III nuclear surveillance may additionally trigger pathophysiological cascades in FTD caused mutations in CHMP2B, another protein implicated in the ESCRT-III pathway. Our proposed research combining the use of super resolution imaging and iPS

Neurodegenerative diseases such as ALS, FTD, and AD share common genetic and pathological underpinnings. We have recently established that CHMP7/ESCRT-III mediated nuclear pore complex injury is an initiating event contributing to TDP-43 dysfunction in sporadic ALS and C9orf72 FTD/ALS. However, the contribution of this injury cascade to other genetic and sporadic forms of FTD and AD remains unknown. Completion of this project will provide essential and novel insights into CHMP2B associated disease pathophysiology and highlight potential therapeutic targets for alleviating injury. Additionally,