Study Supports Cdk5 as Therapeutic Target for ALS

Inhibition of a protein called Cdk5 in the brain increases lifespan and improves motor function in mice with amyotrophic lateral sclerosis (ALS), a new study reports.

This evidence supports a potential role for Cdk5 in the progression of ALS and opens new avenues as a potential therapeutic target for the treatment of this progressive disease.

The study, “Overexpression of the Cdk5 inhibitory peptide in motor neurons rescue of amyotrophic lateral sclerosis phenotype in a mouse model,” was published in the journal Human Molecular Genetics.

Cdk5, an acronym for cyclin-dependent kinase 5, is known for playing a critical role in a number of cellular processes. For example, it is needed to support the brain’s nervous cells’ ability to move into place in the developing brain.

Recently, however, evidence has suggested that this protein also plays a part in neurodegenerative diseases (conditions where nerve cells die). It has been found that Cdk5 is overactive in the brains of people with ALS, Huntington’s, and Alzheimer’s disease, suggesting that blocking its activity could be beneficial in these diseases.

National Institutes of Health (NIH) researchers developed a small protein that had the ability to block Cdk5 activity. They named it Cdk5 inhibitory peptide, or CIP. This small protein specifically blocks Cdk5 only when it is linked to another protein, called p25, which can also contribute to nerve cells’ degeneration.

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To explore the therapeutic potential of CIP, researchers genetically engineered mice to produce high levels of CIP in their motor neurons (the nerve cells predominantly affected by ALS), and confirmed that they had abnormally low Cdk5 activity. In contrast, mice that had ALS due to a mutation in the SOD1 gene had abnormally high Cdk5 activity.

Next, the team crossed the two mouse strains, creating mice that had both ALS and high CIP levels. The researchers named these TriTg mice.

The TriTg mice showed to have significantly lower activation of the Cdk5-p25 protein complex, reaching values closer to control animals without the disease. In addition, they had significantly lower levels of neuroinflammation in the brain and spinal cord, as well as reduced activation of proteins commonly associated with ALS progression.

Further analysis confirmed that the presence of CIP in nerve cells could protect the cells from death, with TriTg mice having approximately twice the number of healthy nerve cells compared to ALS mice.

Overall, TriTg mice lived significantly longer compared to ALS mice, with median survival of 189 days compared to 163 days, representing a 16% increase in lifespan. TriTg mice also had significantly stronger grips, and tended to have fewer motor defects and less muscle atrophy.

“The overexpression of CIP in the motor neurons significantly improves motor deficits, extends survival, and delays pathology in brain and spinal cord of TriTg mice,” researchers stated in summary of their results.

They say that these findings add further evidence and act as proof of concept for the inhibition of Cdk5 as a therapeutic strategy for the treatment of ALS.