Scientists at the University of Utrecht in the Netherlands say they have discovered a new way in which the toxic protein aggregates associated with Huntington’s disease can damage nerve cells and cause them to die.
The study “Nuclear polyglutamine aggregates disrupt the nuclear envelope and hinder its repair,” published in Journal of Cell Biology (JCB), suggests that the aggregates can drill holes in the membrane that separates the nucleus from the rest of the cell. This can damage the DNA in the nucleus and alter the activity of neuronal genes.
“Here we show that nuclear polyglutamine aggregates cause blebbing and tears in the nuclear envelope (NE), which are often incompletely repaired. These tears are associated with disruption of the nuclear lamina and lead to the formation of laminar scars. Expansion microscopy allowed resolution of the ultrastructure of nuclear aggregates and revealed polyglutamine fibrils protruding into the cytosol at break sites, suggesting a mechanism for incomplete repair,” the researchers write.
“In addition, we found that NE repair factors frequently accumulated near nuclear aggregates, consistent with stalled repair. These findings suggest that loss of NE integrity caused by nuclear polyQ aggregates is a potential contributing factor to Huntington’s disease and other polyglutamine disorders.”
Disturbance due to mutation in HTT gene
Huntington’s disease is a devastating neurodegenerative disease caused by a mutation in the HTT Gene that causes cells to produce abnormally large amounts of the huntingtin protein. These enlarged huntingtin proteins accumulate in cells and damage them in various ways, although it is still unclear how exactly this causes nerve cell death.
The team led by Giel Korsten, a PhD student in the group of Dr. Lukas Kapitein, professor of molecular and cellular biophysics and director of the Biology Imaging Center in Utrecht, discovered something different in the way huntingtin aggregates damage cells when they studied neurons expressing the expanded version of the protein. They found that many of the nerve cells had breaks in the membrane that separates the nucleus from the rest of the cell. This nuclear envelope 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 in the nucleus disrupt the protein meshwork that underlies and strengthens the nuclear envelope, making the membrane more prone to rupture. Using expansion microscopy, the researchers were able to visualize the nuclear aggregates in detail and saw tiny fibrils protruding from the aggregates and piercing the meshwork beneath the nuclear envelope. The aggregates may also impair the cell’s ability to reseal the envelope once it ruptures, the researchers found.
“We discovered that the aggregates associated with Huntington’s disease cause cracks in the nuclear envelope, compromising its barrier function,” Kapitein said.
Over time, these nuclear envelope disruptions likely lead to damage to the nerve cell’s DNA and dysregulation of neuronal genes, cellular defects that have already been linked to the pathology of Huntington’s disease.
Kapitein noted that several other neurodegenerative diseases, including certain types of amyotrophic lateral sclerosis and frontotemporal dementia, are associated with the formation of protein aggregates in the cell nucleus.
“We suspect that nuclear envelope ruptures caused by nuclear aggregates are a common factor in neurodegeneration, triggering a cascade of deregulated processes culminating in nerve cell death and neuroinflammation,” Kapitein continued.
