Researchers at Baylor College of Medicine and their collaborators have identified a mechanism linking protein quality control to the breakdown of the nuclear pore in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and certain forms of dementia. Their findings were published in Neuron.
The nuclear pore is a large protein complex made up of about 30 different proteins, forming a channel that allows proteins and RNA to move between the nucleus and 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 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.”
Lloyd’s team investigated how this mislocalization occurs and how the nuclear pore deteriorates. They found that valosin-containing protein (VCP), which normally helps with protein quality control by removing damaged or misfolded proteins, can become overactive in some neurodegenerative diseases.
“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.”
According to their research, excessive VCP activity leads to premature removal of key nuclear pore proteins, destabilizing the structure and contributing to TDP-43 mislocalization as well as neuronal damage.
The mechanism was confirmed across several model systems, including fruit flies and human-derived neurons. In animal models with VCP disease, partially inhibiting VCP restored nuclear pore integrity and improved climbing ability—offering evidence that excessive VCP activity causes these diseases but can be reduced safely.
Lloyd emphasized that further research is necessary before considering existing VCP inhibitors used for cancer treatment as potential therapies for neurodegenerative conditions.
“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 included Sandeep Dubey, Divya Chaubey, Wen-Wen Lin, Hugo J. Bellen (all affiliated with Baylor College of Medicine or Duncan NRI), as well as Chiseko Ikenaga from Johns Hopkins University.
Baylor College of Medicine operates independently within Houston's Texas Medical Center while focusing on research, education across various health disciplines, patient care through partnerships, and community service initiatives according to its official website. The institution has advanced biomedical research since its founding in 1900 and continues these efforts today.
