Scientists at the Utrecht University in the Netherlands say they have identified a new way in which the toxic protein aggregates associated with Huntington’s disease may damage nerve cells and cause them to die.
The study “Nuclear poly-glutamine aggregates rupture the nuclear envelope and hinder its repair,” published in the Journal of Cell Biology (JCB), suggests that the aggregates can 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.
“Here, we show that nuclear polyglutamine aggregates induce nuclear envelope (NE) blebbing and ruptures that are often repaired incompletely. These ruptures coincide with disruptions of the nuclear lamina and lead to lamina scar formation. Expansion microscopy enabled resolving the ultrastructure of nuclear aggregates and revealed polyglutamine fibrils sticking into the cytosol at rupture sites, suggesting a mechanism for incomplete repair,” write the investigators.
“Furthermore, we found that NE repair factors often accumulated near nuclear aggregates, consistent with stalled repair. These findings implicate nuclear polyQ aggregate-induced loss of NE integrity as a potential contributing factor to Huntington’s disease and other polyglutamine diseases.”
Disorder caused by mutation in the HTT gene
Huntington’s disease is a devastating neurogenerative 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 team, led by grad student Giel Korsten from the group of Lukas Kapitein, PhD, a professor of molecular and cellular biophysics and director of the Biology Imaging Center at Utrecht, discovered something different in how huntingtin aggregates damage cells when they examined 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 noted that huntingtin aggregates inside the nucleus disrupt the protein meshwork that underlies and strengthens the nuclear envelope, making the membrane more likely to rupture. Using expansion microscopy to visualize the nuclear aggregates in high detail, the researchers saw that tiny fibrils stick out from the aggregates and poke through the meshwork underlying the nuclear envelope. The aggregates may also impair the cell’s ability to reseal the envelope once it breaks, the researchers found.
“We have discovered that the aggregates associated with Huntington’s disease induce ruptures in the nuclear envelope that compromise its barrier function,” said Kapitein.
Over time, these disruptions in the nuclear envelope likely lead to damage of the nerve cell’s DNA and the misregulation of neuronal genes, cellular defects that have previously been linked to Huntington’s disease pathology.
Kapitein noted that several other neurogenerative diseases, including certain types of amyotrophic lateral sclerosis and frontotemporal dementia, are associated with the formation of protein aggregates inside the cell nucleus.
“We 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,” continued Kapitein.
