- Research led by Dr. Teresa Iglesias from the IIBM uncovers for the first time that the neuroprotective protein PKD1 is decreased in neurons from patients with Huntington’s disease
- The findings, published in the journal Cell Death & Disease, suggest that restoring PKD1 expression in neurons opens new avenues for developing targeted therapies not only for Huntington’s disease but also for other neurodegenerative conditions
A research team at the Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM, CSIC-UAM), led by Teresa Iglesias in collaboration with José J. Lucas’s group at the Centro de Biología Molecular Severo Ochoa (CBM, CSIC-UAM), has made a significant advance in understanding the molecular mechanisms involved in Huntington’s disease. This hereditary neurodegenerative disorder affects the central nervous system, typically manifests between the ages of 30 and 50, has no cure, and has an average survival of 15–20 years after diagnosis, during which patients experience progressive deterioration of their motor, cognitive, and behavioral functions. The disease begins with the death of neurons in a specific brain region called the striatum, and its early symptoms include involuntary movements, clumsiness, and balance problems.
The study, published in Cell Death & Disease, is the result of a collaboration between these two teams and two additional research groups at the CBM — led by Eva Porlan and Miguel R. Campanero — within the framework of the Centro de Investigación Biomédica en Red (CIBER, ISCIII), specifically in the areas of Neurodegenerative Diseases (CIBERNED) and Cardiovascular Diseases (CIBERCV).
Co-author Ana Simón reports that the protein kinase D1 (PKD1) is significantly reduced in neurons from both postmortem brain tissue of Huntington’s patients and mouse models of the disease. “What surprised us,” says Simón, “was discovering that although PKD1 levels drop in neurons, they are increased in other brain cell types, such as astrocytes.” José Lucas adds that these findings point to a complex regulation of PKD1 in Huntington’s disease, with variations depending on cell type and brain region.
PKD1: a protein with neuroprotective potential
Excitotoxicity — neuronal damage caused by overstimulation with the excitatory neurotransmitter glutamate — is a common mechanism in many neurodegenerative diseases. Previous studies by Teresa Iglesias’s group, focused on neuronal death after stroke, showed that this overstimulation deactivates an antioxidant pathway regulated by PKD1 that is essential for neuronal survival. Without this pathway, neurons lose their ability to counteract oxidative stress, which accelerates cell death. Restoring PKD1 activity, on the other hand, reactivates antioxidant defenses and protects neurons from oxidative damage.
This finding laid the groundwork for the current study, which reveals for the first time that PKD1 plays a key role in the particular vulnerability of striatal neurons — the brain region most affected in Huntington’s disease — to this type of damage.
To study PKD1’s neuroprotective role, the researchers used primary cultures of striatal neurons. When PKD1 was inhibited with a specific drug, excitotoxicity-induced cell death increased markedly. In contrast, the application of a molecular tool developed by Teresa Iglesias’s group — designed to selectively activate PKD1 in neurons — resulted in a remarkable resistance to cell death. These results confirm that PKD1 activity is crucial for the survival of striatal neurons and suggest that its loss contributes to early neuronal decline in Huntington’s disease, thereby accelerating the progressive neurodegeneration characteristic of this devastating disorder.
Potential therapeutic applications
The most compelling results came from applying the PKD1-activating molecular tool directly into the striatum of a mouse model of Huntington’s disease.
The neurons that received and expressed the active protein throughout disease progression showed significantly higher levels of molecular markers characteristic of healthy neurons compared to untreated brain regions, demonstrating a clear neuroprotective effect of PKD1. “We believe that boosting PKD1 activity could offer a decisive advantage for the survival of the most vulnerable neurons in this disease,” says Iglesias. Álvaro Sebastián, co-author of the study and currently leading his own research group at the Faculty of Medicine at the Universidad Complutense de Madrid ( UCM), adds: “Uncovering the molecular mechanisms activated by PKD1 to protect neurons could have major implications for other neurological disorders as well.”
The researchers emphasize the urgent need to advance research into Huntington’s disease — a rare condition for which no effective treatments currently exist to halt or slow its progression. Its physical, mental, and behavioral deterioration is devastating. In Spain alone, the disease affects more than 4,000 people. These findings open a new path towards the development of alternative therapeutic strategies which, if confirmed in clinical trials, could improve patients’ quality of life and bring hope to affected families.
Given the significance of this work, the CSIC Communication Department has published this press release on its Actualidad web page.
Cover Image: Immunofluorescence image of cultured striatal neurons; PKD1 protein in yellow. / Ana Simón (IIBM)
Álvaro Sebastián-Serrano*, Ana Simón-García*, María Santos-Galindo, Marina Prudencio Sánchez-Carralero, Alberto H.-Alcántara, Cristina Clemente, Julia Pose-Utrilla, Miguel R. Campanero, Eva Porlan, José J. Lucas, and Teresa Iglesias. Down-regulation of neuroprotective Protein Kinase D in Huntington’s disease. Cell Death and Disease. DOI: 10.1038/s41419-025-07688-9