HOUSTON, January 28, 2026 — A molecular cleanup crew gone rogue may be a key driver of neurodegenerative diseases like ALS and certain forms of dementia, researchers have discovered. The surprising twist? It’s not that this protein, called VCP, isn’t working hard enough—it’s working too hard.
Researchers have pinpointed a mechanism linking protein quality control with damage to the nuclear pore, a critical gateway in cells.
- Protein quality control and nuclear pore function are both implicated in neurodegenerative diseases.
- Overactivity of the VCP protein destabilizes the nuclear pore.
- Restoring nuclear pore integrity in animal models improved motor function.
- The findings could open doors to new treatments, potentially repurposing existing cancer drugs.
For years, scientists have understood that problems with protein quality control and the nuclear pore—the cell’s largest protein complex, responsible for shuttling vital molecules—play a role in conditions like amyotrophic lateral sclerosis (ALS) and dementia. But the connection between these two issues remained murky. Now, a team at Baylor College of Medicine has illuminated the link, publishing their findings in the latest edition of Neuron.
VCP Overdrive: A Breakdown in Cellular Traffic
The nuclear pore, composed of roughly 30 different proteins, acts as a tightly regulated channel, controlling the movement of proteins and RNA between the cell’s nucleus and its cytoplasm. Disruptions to this process can have devastating consequences.
“We have known for more than a decade that this site plays a role in neurodegenerative disease,” explained 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. “A hallmark is abnormal behavior of a protein called TDP-43. In ALS and many dementias, TDP-43 isn’t trafficking through the nuclear pore properly. It’s lost from the nucleus and accumulates in toxic aggregates in the cytoplasm, leading to both a loss of function and a toxic gain of function.”
But what exactly throws a wrench into TDP-43’s normal journey through the nuclear pore?
The answer, according to Lloyd and his colleagues, lies with valosin-containing protein (VCP). “VCP is an essential protein found in all cells, from yeast to humans,” Lloyd said. “Its normal role is quality control—recognizing damaged or misfolded proteins and extracting them. In this way, VCP acts as a molecular cleanup crew.”
The researchers discovered that in VCP disease, overactive VCP prematurely removes key proteins that form the nuclear pore, marking them for degradation. This destabilizes and impairs the pore’s function, disrupting TDP-43 transport and ultimately causing neuronal damage.
The team validated this mechanism across a range of model systems, from fruit flies to human-derived neurons. Critically, in animal models of VCP disease, partially inhibiting VCP restored nuclear pore integrity and improved climbing ability—the first evidence in living animals that excessive VCP activity drives the disease and that reducing this activity can be beneficial.
Lloyd emphasized that further research is needed to determine if VCP inhibitors, currently used in cancer treatment, could be repurposed to treat neurodegenerative diseases. “Protein degradation is a double-edged sword,” he cautioned. “Too much degradation is harmful in VCP disease, while too little contributes to toxic protein buildup in other neurodegenerative disorders. We can’t broadly block VCP. 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.”
Collaborators on this study included 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.
Q&A: What does this mean for people with ALS or dementia? This research identifies a specific molecular mechanism—overactive VCP—that contributes to neurodegeneration. While a treatment isn’t available yet, the findings suggest that targeting VCP activity could be a promising therapeutic strategy, potentially by repurposing existing drugs.
