Scientists have identified evidence of a previously unknown process that may explain how brain cells die in Alzheimer’s disease and frontotemporal dementia (FTD). The discovery, centered around a mechanism known as karyoptosis, could point researchers to new ways to slow the progression of these devastating conditions.
Many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and FTD, are characterized by the accumulation of harmful proteins within neurons. Over time, these nerve cells die, causing memory loss and other symptoms. Although scientists have long known about several forms of cell death, including apoptosis, those mechanisms never fully explained the widespread neuron loss seen in these diseases.
Now, researchers from King’s College London, in collaboration with the UK Dementia Research Institute and with some support from Alzheimer’s Research UK, have identified karyocytosis as a potential missing link leading to toxic protein build-up and brain cell death.
Nuclear drop syndrome refers to a series of chemical reactions that are initiated when toxic proteins accumulate inside cells. As this process progresses, the cell nucleus containing the genetic material gradually shrinks and eventually falls apart.
Evidence found in Alzheimer’s disease and FTD brains
The survey results are nature communicationsbased on an analysis of 3,000 brain cells taken from 28 people with either FTD or late-stage Alzheimer’s disease. The researchers used computational algorithms to identify the different forms of cell death that occur within tissues.
They found signs of nuclear ptosis in 35 percent of cells in the frontal lobes of Alzheimer’s patients, but only 15 percent of cells from healthy older adults.
“This study is the culmination of 10 years of research at King’s, from first identifying nuclear ptosis, a relatively rare disease, to discovering that it is a common feature of dementia, which affects millions of people.”
Possibility of new target for dementia treatment
The researchers also uncovered important molecular pathways that appear to control nucleotosis. They found that forcing proteins in neurons to aggregate, a hallmark of many neurodegenerative diseases, can trigger this destructive process.
Studies show that the buildup of toxic proteins destabilizes the outer membrane of the nucleus, causing the cell nucleus to shrink and eventually collapse.
The team then studied proteins known as kinases, which act as molecular switches in this pathway. In experiments using rat neurons, blocking these switches reduced markers associated with nuclear ptosis. In particular, the interaction between the kinase p38 MAP kinase and the protein LaminB1 has emerged as a promising target for slowing or preventing nuclear destruction.
Researchers believe this pathway could eventually lead to treatments that reduce brain cell loss in dementia. Their next goal is to develop a method to selectively target the interaction between p38 MAP kinase and LaminB1 in humans.
“By specifically targeting the interaction between p38 MAP kinase and lamin B1, we may be able to slow down the cell death process and buy time for more precise treatments for certain neurodegenerative diseases,” said Dr. Manolis Fant, leader of functional genomics at the Institute of Psychiatry, Psychology and Neuroscience at King’s College London.
Building a roadmap for future treatments
“The death and loss of cells in the brain causes many of the symptoms experienced by dementia patients. Our research has uncovered a new set of chemical phenomena that may modulate cell death in brain cells. We are excited about the potential future breakthroughs this will lead to in the dementia research community and beyond,” said Dr Rebecca Casterton, senior research fellow at the King’s Dementia Research Institute in the UK and lead author of the paper.
“Although we’ve known for decades that toxic proteins accumulate in Alzheimer’s disease and frontotemporal dementia, it remained unclear exactly how they lead to brain cell loss.
Dr Sarah Rodriguez, Senior Research Manager at Alzheimer’s Research UK, said: “Identification of nuclear ophthalmia is an important step in finding therapeutic targets that can stop or slow cell loss. This could help widen the range of treatments that tackle the root causes of the disease and bring us closer to a cure for dementia. This is why Alzheimer’s Research UK is funding and supporting the research.”
The study that “nucleocytosis mediates cell death and neurodegeneration due to proteotoxic stress” nature communications.
This research was primarily funded by Alzheimer’s Research UK and the Biotechnology and Biological Sciences Research Council International Partnership. Additional support was provided by studentships provided by the UK Medical Research Council and Dementia Research UK.
