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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 at Baylor College of Medicine and their colleagues 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 Dr. Thomas E. Lloyd, professor and chair of the Department of Neurology at Baylor and a researcher at the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital. "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."

So how does this mislocalization happen and how does the nuclear pore break down?

Lloyd and his colleagues were able to identify 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 protein quality control by recognizing damaged or misfolded proteins and extracting them," Lloyd said. "In this way, VCP acts as a molecular cleanup crew."

He and his collaborators 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 mislocalization of TDP-43 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 rescued climbing ability, providing some of the first in vivo evidence that VCP disease is caused by excessive VCP activity and that this activity can be safely reduced.

Lloyd 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," Lloyd said. "We have 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."

Collaborators on this study include Sandeep Dubey , Divya Chaubey, Wen-Wen Lin, Hugo J. Bellen, all with Baylor College of Medicine and/or the Duncan NRI, and Chiseko Ikenaga, Johns Hopkins University.
For full funding information please see publication acknowledgments.