Researchers Identify How a “Quality Control” Protein Causes Neurodegenerative Disease

HOUSTON (Jan. 14, 2026) – 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 the Texas Children’s Duncan Neurological Research Institute (NRI) 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, researcher at Texas Children’s Duncan NRI and professor and chair of the Department of Neurology at Baylor. “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 Duncan NRI and/or Baylor College of Medicine, and Chiseko Ikenaga, Johns Hopkins University.

About Texas Children’s 
Texas Children's, a nonprofit health care organization, is committed to creating a healthier future for children and women throughout the global community by leading in patient care, education and research. Consistently ranked as the best children's hospital in Texas and among the top in the nation, Texas Children's has garnered widespread recognition for its expertise and breakthroughs in pediatric and women's health. The system includes the Texas Children's Duncan NRI; the Feigin Tower for pediatric research; Texas Children's Pavilion for Women, a comprehensive obstetrics/gynecology facility focusing on high-risk births; Texas Children's Hospital West Campus, a community hospital in suburban West Houston; Texas Children's Hospital The Woodlands, the first hospital devoted to children's care for communities north of Houston and Texas Children's Hospital North Austin, the new state-of-the-art facility providing world-class pediatric and maternal care to Austin families. The organization also created Texas Children's Health Plan, the nation's first HMO focused on children; Texas Children's Pediatrics, the largest pediatric primary care network in the country; Texas Children's Urgent Care clinics that specialize in after-hours care tailored specifically for children; and a global health program that is channeling care to children and women all over the world. Texas Children's Hospital is affiliated with Baylor College of Medicine. For more information, visit www.texaschildrens.org.