Discovery of karyoptosis opens new therapeutic targets for Alzheimer’s and frontotemporal dementia

Researchers at King’s College London and the UK Dementia Research Institute have identified karyoptosis, a new cell death mechanism found in patients with Alzheimer’s disease and frontotemporal dementia (FTD). According to a study published in Nature Communications, toxic protein accumulation triggers a chemical reaction that causes the cell nucleus to shrivel and disintegrate.

This process provides a potential link between the buildup of toxic proteins and the death of neurons. While apoptosis is a known form of cell death, researchers found it does not account for all neuronal loss in neurodegenerative diseases like Alzheimer’s, FTD, and amyotrophic lateral sclerosis (ALS).

How does karyoptosis cause brain cell loss?

Karyoptosis occurs when toxic levels of proteins accumulate inside neurons, causing the outer layer of the nucleus to become unstable. This instability leads the nucleus—the area containing genetic information—to shrivel before it eventually disintegrates.

Dr. Rebecca Casterton, a senior researcher at the UK Dementia Research Institute at King’s, stated the study uncovers a new series of chemical events that coordinate cell death in brain cells. She described the findings as a “road map” of how the process works.

What did the research reveal about dementia markers?

The study used computational algorithms to analyze brain cells from patients with FTD and terminal stage Alzheimer’s. This research was the result of a 10-year effort at King’s College London, moving from the identification of karyoptosis in a rare disease to its discovery in common dementias.

Researchers identified a specific pathway controlled by proteins that act as “switches,” known as kinases. Specifically, the interaction between a protein called LaminB1 and p38 MAP kinase was identified as a key target for slowing nuclear disintegration.

How could this lead to new dementia treatments?

By targeting the interaction between p38 MAP kinase and LaminB1, researchers were able to reduce karyoptosis markers in rat neurons in a dish. Dr. Manolis Fanto, Reader in Functional Genomics at King’s College London, said this approach may slow the process of cell death.

Slowing this process could buy time for more pinpointed therapies against specific neurodegenerative diseases. Dr. Sara Rodrigues, Senior Research Manager at Alzheimer’s Research UK, stated that identifying karyoptosis is a crucial step toward finding treatments that could stop or slow cell loss.

Future work may focus on selectively targeting the protein-kinase interaction to produce viable treatment targets for humans. This could potentially widen the window for therapies that tackle the underlying causes of dementia, according to Dr. Rodrigues.

The work was funded by Alzheimer’s Research UK, the Biotechnology and Biological Sciences Research Council International Partnership, the UK Medical Research Institute, and the UK Dementia Research Institute. More details are available via the study’s DOI: 10.1038/s41467-026-73802-w.

Frequently Asked Questions

What is karyoptosis?
Karyoptosis is a set of chemical reactions triggered by the accumulation of toxic proteins that cause the cell nucleus to shrivel and disintegrate, ultimately leading to cell death.

Which diseases are associated with this mechanism?
Markers of karyoptosis have been found in the brains of patients with Alzheimer’s disease and frontotemporal dementia (FTD), and it is linked to the toxic protein accumulation seen in diseases such as amyotrophic lateral sclerosis (ALS).

How did researchers test the prevention of karyoptosis?
Researchers targeted the interaction between p38 MAP kinase and the protein LaminB1, which successfully reduced levels of karyoptosis markers in rat neurons in a dish.

How might the discovery of new cell death mechanisms change the way we approach dementia treatment?