Aberrant nuclear pore complex degradation contributes to neurodegeneration
When it comes to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and certain forms of dementia, researchers have known that protein quality control and damage to the nuclear pore are key players. However, how the two are connected has not been clear. Researchers have now identified the mechanism that links the two. The findings are published in the latest edition of Neuron.
The nuclear pore, the largest protein complex in the cell, is made up of roughly 30 different proteins. It forms a tightly regulated channel, allowing proteins and RNA to move between the nucleus and the cytoplasm.
“We have known for more than a decade that this site plays a role in neurodegenerative disease. A hallmark is abnormal behavior of a protein called TDP-43,” said the senior auhtor. “In ALS and many dementias, TDP-43 is not trafficking through the nuclear pore properly. It is lost from the nucleus and accumulates in toxic aggregates in the cytoplasm. This creates two issues – loss of its normal nuclear function and gain of toxic function in the cytoplasm.”
But, what disrupts TDP-43 normal trafficking through the nuclear pore?
The researchers have identified valosin-containing protein (VCP) as a central player in this process.
“VCP is an essential protein found in all cells, from yeast to humans. Its normal role is quality control by recognizing damaged or misfolded proteins and extracting them,” the author said. “In this way, VCP acts as a molecular cleanup crew.”
The researchers discovered that in some neurodegenerative diseases called "VCP disease", the problem is not too little VCP activity, but too much. Overactive VCP prematurely removes key proteins that make up the nuclear pore and sends them for degradation. As a result, the nuclear pore becomes destabilized and dysfunctional, contributing to the disruption of TDP-43 transport and neuronal damage.
The team confirmed the same mechanism across multiple model systems, ranging from fruit flies to human-derived neurons. In animal models of VCP disease, partially inhibiting VCP restored nuclear pore integrity and restored climbing ability, providing some of the first evidence in live animals that VCP disease is caused by excessive VCP activity and that this activity can be safely reduced.
The senior author says more research is needed to understand how VCP inhibitors that already are in use for cancer treatment could one day be used to treat neurodegenerative disease.
“Protein degradation is a double-edged sword. Too much degradation is harmful in VCP disease, too little degradation contributes to toxic protein buildup in other neurodegenerative disorders. We can’t broadly block VCP,” the author said. “It’s important to understand how VCP and its adaptor proteins maintain the nuclear pore. Together, these efforts open the door to new strategies for protecting the nuclear pore and potentially slowing or preventing neurodegeneration.”
