Cdk5 enzyme may be promising therapeutic target for SMA

Inhibiting hyperactive protein lessens motor neuron degeneration in early study

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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Inhibiting an abnormally hyperactive protein called cyclin-dependent kinase 5 (Cdk5) significantly lessens the dysfunction and death of motor neurons, the cells lost in spinal muscular atrophy (SMA), a new study reports.

These findings support Cdk5 as a potential therapeutic target for the progressive disease, researchers say.

The study, “Mitigating aberrant Cdk5 activation alleviates mitochondrial defects and motor neuron disease symptoms in spinal muscular atrophy,” was published in the journal PNAS.

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SMA comprises a group of neurodegenerative disorders that are characterized by progressive muscle weakness and atrophy (shrinkage) due to the loss of motor neurons, which are the nerve cells that control voluntary muscle movement.

The main cause is mutations in the SMN1 gene, which provides instructions for making the SMN protein that is essential for motor neuron survival.

In the last decade, there have been marked advances in SMA treatments, including the development of gene therapies, which in general work by providing a healthy version of SMN1, allowing cells to produce their own functional SMN protein.

However, “current therapies can only help a subset of patients and for some treatments, such as gene therapy, there’s already evidence that it may have strong side effects in the long-term,” Yongchao C. Ma, PhD, associate professor of pediatrics and neuroscience at Northwestern University Feinberg School of Medicine, and the study’s lead author, said in a university news story.

Moreover, the causes of nerve cell death in SMA, which are still largely unknown, have “long been a question my lab is interested in,” Ma said.

Cdk5 causes defects in mitochondria, promotes death of motor neurons in SMA

In the study, Ma and his team discovered that Cdk5 causes defects in mitochondria, which are the organelles that generate energy for cells, and promotes the death of motor neurons in SMA.

Cdk5 plays a critical role during the development of the central nervous system consisting of the brain and spinal cord.

Using induced pluripotent stem cells (iPSCs) from patients with SMA and mouse models of the disease, the researchers observed these cells had a significant increase in Cdk5 activity. (Of note, iPSCs are fully matured cells that can be reprogrammed back to a stem-cell state, from which they are able to grow into almost any type of cell.)

Importantly, the increase of Cdk5 activity occurred before the onset of SMA symptoms, “suggesting that it may be an initiator of the disease,” the researchers wrote.

The team reduced Cdk5 activity in an SMA mouse model by deleting the gene carrying the instructions for the kinase. The results showed the mitochondrial defects typically seen in these animals were no longer visible, and the disease symptoms were significantly lessened.

“In this study, we’ve identified an unexpected role of Cdk5 signaling in causing mitochondrial defects and selective motor neuron degeneration in SMA,” Ma said.

Specifically, increased CDk5 activity resulted in a loss of the mitochondria’s ability to control calcium levels, which can lead to motor neuron death.

Reducing the kinase activity led to a significant easing of motor neuron dysfunction, including their hyperexcitability (when they generate electrical signals more readily than normal), and the loss of communication with other motor neurons, as well as between motor neurons and muscles.

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Reducing Cdk5 activity decreases motor neuron degeneration in lab studies

Similar findings were observed in lab studies using a pharmacological inhibitor of Cdk5 activity in motor neurons derived from SMA mice and human SMA iPSC disease models. Overall, reducing Cdk5 activity decreased motor neuron degeneration.

“Based on our genetic rescue in both mouse models and in human induced pluripotent stem cell disease models, it really suggests a novel pathogenic [disease] mechanism and new therapeutic strategy for SMA,” Ma said.

Current available Cdk5 inhibitors not only have toxic side effects, but also are not specific for Cdk5. Ma and his team are now working to develop a new, highly specific inhibitor for Cdk5, as a way to reduce motor neuron degeneration.

Rescuing Cdk5 normal activity by targeting other molecular players regulated by Cdk5 is another strategy the lab is pursuing.

Overall, since mitochondria dysfunction is also seen in other motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), restoring its functions “may help patients with SMA or ALS, and would be a completely new direction for treatment,” Ma said.