Excessive VCP Intake Linked to Neurodegenerative Disease

Researchers identify mechanism connecting protein quality control and nuclear pore dysfunction in ALS and dementia.

Jan. 27, 2026 at 10:55pm

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Researchers at Baylor College of Medicine have discovered that overactive valosin-containing protein (VCP), an essential protein involved in quality control by recognizing and degrading damaged or misfolded proteins, can prematurely remove key proteins that make up the nuclear pore. This destabilizes the nuclear pore and disrupts the normal trafficking of the protein TDP-43, which is a hallmark of amyotrophic lateral sclerosis (ALS) and certain forms of dementia.

Why it matters

The findings provide new insights into the mechanisms underlying neurodegenerative diseases like ALS and dementia, which are characterized by the abnormal behavior of TDP-43. Understanding how excessive VCP activity contributes to nuclear pore dysfunction and TDP-43 mislocalization could lead to new strategies for protecting the nuclear pore and potentially slowing or preventing neurodegeneration.

The details

The nuclear pore is the largest protein complex in the cell, made up of around 30 different proteins that form a tightly regulated channel allowing proteins and RNA to move between the nucleus and cytoplasm. In neurodegenerative diseases, the protein TDP-43 is not trafficking properly through the nuclear pore, leading to its loss from the nucleus and accumulation in toxic aggregates in the cytoplasm. The researchers found that overactive VCP, a protein involved in quality control by recognizing and degrading damaged proteins, prematurely removes key nuclear pore proteins, destabilizing the pore and disrupting TDP-43 transport.

  • The findings were published in the latest edition of the journal Neuron.

The players

Dr. Thomas E. Lloyd

Professor and chair of the Department of Neurology at Baylor College of Medicine and a researcher at the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

Valosin-containing protein (VCP)

An essential protein found in all cells from yeast to humans, whose normal role is quality control by recognizing and degrading damaged or misfolded proteins.

TDP-43

A protein that is a hallmark of amyotrophic lateral sclerosis (ALS) and certain forms of dementia, where it is not trafficking properly through the nuclear pore, leading to its loss from the nucleus and accumulation in toxic aggregates in the cytoplasm.

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What they’re saying

“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.”

— Dr. Thomas E. Lloyd, Professor and chair of the Department of Neurology at Baylor (Mirage News)

“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.”

— Dr. Thomas E. Lloyd, Professor and chair of the Department of Neurology at Baylor (Mirage News)

“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.”

— Dr. Thomas E. Lloyd, Professor and chair of the Department of Neurology at Baylor (Mirage News)

What’s next

More research is needed to understand how VCP inhibitors that are already in use for cancer treatment could one day be used to treat neurodegenerative diseases by safely reducing excessive VCP activity.

The takeaway

The findings provide new insights into the mechanisms underlying neurodegenerative diseases like ALS and dementia, opening the door to potential new strategies for protecting the nuclear pore and slowing or preventing neurodegeneration.