New ALS study suggests targeting VCP could protect nerve cells
Study centers on ALS linked to VCP mutations and nuclear pore changes
- In rare genetic ALS tied to VCP mutations, an overactive “cleanup” system may damage nerve cells.
- The study links VCP overactivity to nuclear pore disruption and abnormal TDP-43 location in cells.
- Blocking VCP improved movement in lab models, pointing to a potential treatment strategy.
Overactivity of a molecular system that normally helps clear unwanted proteins may contribute to nerve cell damage in certain genetic forms of amyotrophic lateral sclerosis (ALS), a new study suggests.
The findings may open new avenues for treatment, researchers wrote in the study titled “Aberrant nuclear pore complex degradation contributes to neurodegeneration in VCP disease,” published in Neuron.
In ALS, nerve cells that control voluntary movement become progressively damaged and die. The causes of ALS are not fully understood, but some cases are linked to inherited gene mutations.
VCP mutations are tied to rare genetic forms of ALS
Mutations in the gene that encodes the valosin-containing protein (VCP) are associated with ALS. Mutations in this gene have also been reported in families with other neurological diseases, including Parkinson’s disease and Alzheimer’s.
“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,” Thomas Lloyd, MD, PhD, co-author of the study at Baylor College of Medicine, said in a news story. “In this way, VCP acts as a molecular cleanup crew.”
In this study, scientists uncovered a previously unappreciated way that abnormal VCP can harm nerve cells. Using experiments in cell models, human-derived neurons, and fruit flies, the researchers showed that VCP helps regulate proteins that make up the nuclear pore complex.
The nucleus is the compartment that houses a cell’s DNA. Because DNA is essential for cell function, the nucleus is built like a vault designed to protect it. The nuclear pore complex acts like a set of gates in the nuclear envelope, helping control what moves in and out of the nucleus.
Previous research suggests defects in nuclear pore function may play a role in ALS. In many people with the disease, a protein called TDP-43, which normally works in the nucleus, is found outside it, where it can build up into toxic clumps in the cytoplasm (the fluid inside cells).
“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,” Lloyd said. “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.”
Overactive VCP may damage the cell’s nuclear pores
The new findings suggest that VCP mutations may contribute to nuclear pore complex dysfunction in ALS. Specifically, the researchers found that VCP normally helps regulate the turnover and removal of certain nuclear pore proteins. But in disease-causing forms of VCP, the protein becomes overactive, leading to excessive breakdown of nuclear pore components.
This abnormal breakdown may contribute to ALS and other VCP-related neurological diseases, the researchers said. In fruit flies, inhibiting VCP helped normalize nuclear pore protein levels and improved movement.
If these findings hold up in future studies, targeting VCP could be a potential strategy for some VCP-related neurodegenerative diseases, including certain forms of ALS.
“We provide multiple lines of evidence suggesting that disease-associated mutations in VCP cause [nerve cell damage] by altering [nuclear pore complexes],” the researchers concluded, adding that these findings “have implications for therapeutics” in ALS and other neurodegenerative diseases.
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