Researchers at Utrecht University have discovered a new mechanism by which Huntington’s disease causes neuronal death. They found that toxic protein aggregates from a mutated huntingtin protein can damage the nuclear envelope, leading to DNA damage and gene misregulation in neurons.
The study reveals that the aggregates poke holes in the membrane that separates the nucleus from the rest of the cell, damaging the DNA inside the nucleus and changing the activity of neuronal genes. This breakthrough could link similar mechanisms to other neurodegenerative diseases, suggesting a common pathway for neuronal damage and offering potential new targets for therapeutic intervention.
Huntington’s disease is a devastating neurodegenerative disorder caused by a mutation in the HTT gene that results in cells producing abnormally large versions of the huntingtin protein. These expanded huntingtin proteins aggregate inside cells and damage them in various ways, although exactly how this results in the death of nerve cells remains uncertain.
The researchers found that many of the nerve cells had breaks in the membrane that separates the nucleus from the rest of the cell, known as the nuclear envelope. This barrier protects and regulates the chromosomes inside the nucleus, allowing them to turn genes on and off as needed.
Kapitein and colleagues found that huntingtin aggregates inside the nucleus disrupt the protein meshwork that underlies and strengthens the nuclear envelope, making the membrane more likely to rupture. They also found that these disruptions can impair the cell’s ability to reseal the envelope once it breaks, leading to damage of the nerve cell’s DNA and the misregulation of neuronal genes.
This discovery could have broader implications for neurodegenerative diseases, including certain types of amyotrophic lateral sclerosis and frontotemporal dementia. The researchers speculate that nuclear aggregate-induced ruptures in the nuclear envelope represent a common contributor to neurodegeneration that initiates a cascade of deregulated processes culminating in neuronal death and neuroinflammation.
Source: https://scitechdaily.com/mapping-the-molecular-mayhem-caused-by-huntingtons-disease/