A study recently published in the journal Cell Reports identifies a genetic mutation as an additional cause of cerebellar ataxia, a disorder causing uncoordinated muscle movements in humans and animals. The finding could prove useful for pharmaceuticals companies developing drugs for the treatment of neurodegenerative diseases.


The cerebellum is the part of the brain that controls gait and muscle coordination. In the disorder cerebral ataxia, the cerebellum becomes damaged or inflamed. This in turn results in the loss of ability to coordinate muscular movement. There are several genes involved in the control of movement of muscles by motor neurons that can be associated with ataxia when mutated. In a recent study, the findings of which were published in Cell Reports, Baudry and colleagues have identified in mice another cause of cerebral ataxia — genetic mutation in, or deletion of, the enzyme calpain-1. The mutation or deletion in the gene CAPN1 that encodes for the enzyme calpain-1 was found to disrupt the enzyme’s function and cause abnormal cerebellar development.

The calpain enzyme is involved with memory, learning and synaptic plasticity in the brain, and it exists in two major forms— calpain-1 and calpain-2. For three decades now, Baudry and his team have investigated the function of both forms of the enzyme in synaptic plasticity, memory and learning and neurodegeneration. However, since most of the research had used molecules that inhibit both forms of the enzyme at once, very little progress had been made in determining the function of calpain. Nearly 8 years ago, the research team conducted a study using a line of mice genetically engineered to lack calpain-1, demonstrating that calpain-1 had a neuroprotective function, while calpain-2 had a neurodegenerative one. As well, another scientist had identified several families with members that have calpain-1 mutations and display symptoms of cerebellar ataxia, suggesting the association between calpain-1 mutations and ataxia. A published study suggests that calpain-1 mutation was also linked to cerebellar ataxia in Parson Russell Terrier dogs.

In their latest study, Baudry and colleagues examined the process by which the mutation/deletion of calpain-1 results in cerebral ataxia, using calpain-1 knock-out mice (mice in which researchers “knocked out” calpain-1), which the team also found to show a mild form of ataxia. The researchers found that during the early period after birth, the mice missing the calpain-1 enzyme due to the CAPN1 mutation had a much greater level of neuronal death in their cerebellum, and several of their synapses failed to fully mature and develop, compared to normal mice.

During the postnatal period (period after birth), the brain is normally still developing and maturing while producing neurons in excess amounts. The brain then prunes itself and removes neurons that are in excess and non-functional, but calpain-1 prevents this process from getting out of control and is therefore neuroprotective. Among mice lacking calpain-1, the process by which the brain prunes itself and removes excess neurons was out of control, resulting in neuronal death and immature synapses; these mice showed far less neurons in various parts of the brain, including the cerebellum and hippocampus, than normal mice. Therefore, a mutation or deletion in the calpain-1 gene results in an abnormal development of the cerebellum, which is responsible for the ataxia.

The researchers further identified the key target of calpain-1, which is responsible for normally activating a pro-survival pathway — a protein phosphatase called PHLPP1. Calpain-1 functions normally by degrading PHLPP1, which was previously shown to be associated with programmed cell death, or apoptosis. When the researchers addressed the lack of calpain-1 in mice with CAPNI mutations through a pharmacological treatment during the first week after birth, they found that symptoms of cerebellar ataxia were eliminated and development occurred normally.  Symptoms were also eliminated by crossing the calpain-1 knock-out mice with mice lacking PHLPP1, therefore producing double knock-out mice. These double knock-out mice did not have excess loss of neurons and developed normally without ataxia. This shows that calpain-1 is neuroprotective by degrading PHLPP1, and as a result, activating a neuroprotective pathway. Mutations or deletion in the enzyme calpain-1 results in brain abnormalities, which are associated with excessive neurodegeneration and changes in development after birth.

The overall findings of this study suggest that calpain-1 is another gene involved in cerebellar ataxia, and identifies potential treatments for this type of ataxia. As well, they raise critical concerns for pharmaceutical companies attempting to use nonselective calpain inhibitors for the treatment of neurodegenerative diseases. A calpain inhibitor that blocks both calpain-1 and calplain-2, and that does not discriminate between the two enzymes, affects both neurodegeneration and neuroprotection, and therefore, may provide no effects. The researchers assert that calpain-2 inhibitors need to be used to address neurodegeneration, as calpain-2 has been found to have a neurodegenerative role.  The researchers are now working with a new company called NeurAegis to develop selective calpain-2 inhibitors as neuroprotective drugs to treat neurodegeneration.




Written By: Nigar Celep, BASc

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