A possible clue in dementia has come from inside the cell’s nucleus.
Researchers at King’s College London say they have identified evidence of a previously unknown process that may help explain how brain cells die in Alzheimer’s disease and frontotemporal dementia, or FTD. The process, known as karyoptosis, could point to new ways to slow the progression of the diseases.
Many neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer’s disease and FTD, involve the buildup of harmful proteins inside neurons. Scientists have long known about several forms of cell death, including apoptosis, but those mechanisms have not fully explained the scale of neuron loss seen in these disorders.
The team, working with the UK Dementia Research Institute and supported in part by Alzheimer’s Research UK, identified karyoptosis as a possible link between toxic protein buildup and brain cell death. Karyoptosis refers to a series of chemical reactions triggered when toxic proteins accumulate inside a cell. The nucleus then gradually shrivels before breaking apart.
The findings, published in Nature Communications, were based on an analysis of 3,000 brain cells from 28 people with either FTD or end stage Alzheimer’s disease. Using computational algorithms, the researchers identified different forms of cell death in the tissue.
They found signs of karyoptosis in 35 percent of cells from the frontal cortex of people with Alzheimer’s disease, compared with 15 percent of cells from healthy older adults.
“This study is the culmination of a 10-year journey at King’s, from when we first identified karyoptosis in a relatively rare disease to discovering that it is a common feature of dementias which affect millions of people.”
The researchers also identified a molecular pathway that appears to control karyoptosis. They found that forcing proteins inside neurons to clump together can trigger the process. According to the study, the buildup of toxic proteins destabilises the outer membrane of the nucleus, causing it to shrink and then disintegrate.
In laboratory experiments using rat neurons, blocking proteins known as kinases reduced markers linked to karyoptosis. The interaction between p38 MAP kinase and the protein LaminB1 emerged as a target for slowing or preventing the breakdown of the nucleus.
“By specifically targeting the interaction between p38 MAP kinase and LaminB1 we may slow down the process of cell death, buying time for more pinpointed therapies against specific neurodegenerative diseases,” said Dr Manolis Fanto, Reader in Functional Genomics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London.
“The death and loss of cells in the brain drives many symptoms experienced by people living with dementia. Our study uncovers a new series of chemical events which can coordinate cell death in brain cells. We have started to lay out the road map of how karyoptosis works, and I’m excited to see future breakthroughs this may drive in the dementia research community and beyond,” said Dr Rebecca Casterton, senior researcher at the UK Dementia Research Institute at King’s and first author on the paper.
“For decades, we’ve known that toxic proteins build up in Alzheimer’s disease and frontotemporal dementia, but exactly how they lead to the loss of brain cells has remained unclear.
“The identification of karyoptosis is a crucial step towards finding targets for treatments that could stop or slow cell loss. It could help widen the window for therapies that tackle the underlying causes of disease, bringing us closer to a cure for dementia. This is why Alzheimer’s Research UK funds and supports research,” said Dr Sara Rodrigues, senior research manager at Alzheimer’s Research UK.
The study, “Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress,” was primarily funded by Alzheimer’s Research UK and the Biotechnology and Biological Sciences Research Council International Partnership.
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