Researchers at the Texas Children’s Duncan Neurological Research Institute (NRI) and collaborators have identified a mechanism linking protein quality control and nuclear pore damage in neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and specific dementias. These findings were published in the journal Neuron.
Key Discovery
The study focused on the nuclear pore, a substantial protein complex essential for regulating protein and RNA transport between the cell’s nucleus and cytoplasm. In neurodegenerative diseases, the protein TDP-43 exhibits abnormal behavior, migrating from the nucleus and forming toxic aggregates in the cytoplasm. This process is associated with nuclear pore degradation.
The team identified valosin-containing protein (VCP) as a key element in this mechanism. VCP typically functions in protein quality control, removing damaged or misfolded proteins. However, in certain "VCP diseases," overactive VCP prematurely removes essential nuclear pore proteins, leading to their degradation. This action destabilizes and impairs the nuclear pore, which contributes to the mislocalization of TDP-43 and subsequent neuronal damage.
Research Outcomes
The identified mechanism was validated across multiple model systems, including fruit flies and human-derived neurons. In animal models of VCP disease, partial inhibition of VCP led to the restoration of nuclear pore integrity and improved motor abilities. This provides initial in vivo evidence that excessive VCP activity is a cause of VCP disease and that this activity can be safely modulated.
Future Implications
Additional research is required to determine how VCP inhibitors, currently utilized in cancer treatment, could be applied to neurodegenerative diseases. Researchers emphasized that protein degradation balance is critical, and broad VCP blockage may not be beneficial. Understanding how VCP and its associated proteins maintain the nuclear pore is expected to facilitate new strategies for protecting the nuclear pore and potentially mitigating neurodegeneration.