Researchers Explore Caspase-1 as Potential Therapeutic Target for CLN3 Disease

Caspase-1 — an enzyme involved in several cellular processes, including inflammatory responses — is a potential therapeutic target to revert some of the features of CLN3 disease, the juvenile form of Batten disease, according to a mouse study.

The study, “Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis,” was published in the Journal of Neurochemistry.

CLN3 disease is the most common form of Batten disease and is caused by mutations in the CLN3 gene, which provides instructions to make a protein called battenin. Symptom onset occurs between 5 and 10 years of age, and often begins with progressive blindness and seizures, followed by motor and cognitive deterioration.

The disease is characterized by the toxic accumulation of molecules inside lysosomes — cellular structures responsible for breaking down waste — which mainly affect brain cells. However, recent evidence suggests that lysosomal waste accumulation is not a direct cause of neurodegeneration in juvenile Batten disease.

Another hallmark of this disease is the abnormal activation of astrocytes and microglia — cells located in the central nervous system that are involved in the support and protection of nerve cells — in the brains of both patients and mouse models of the disease.

While the biological function of battenin remains unclear, it has been involved in lysosomal activity, mitochondrial function (cells’ powerhouses), and cell death, among other processes. In addition, increased levels of inflammatory molecules have been observed in the brain of a mouse model of CLN3 disease (animals lacking the CLN3 gene).

Recent findings have shown a link between lysosomal and mitochondrial dysfunction and the activation of caspase-1 in several diseases, including Alzheimer’s disease, atherosclerosis, and spinal cord injury. Caspase-1 is an enzyme involved in several cellular processes, including the production of inflammatory molecules, cell death, and lysosomal, mitochondrial and nerve cell function.

Excessive activation of caspase-1 also is present in microglial cells of a mouse model of CLN3 disease, suggesting that this enzyme may have a role in the development of the disease.

Researchers at University of Nebraska Medical Center evaluated the effects of caspase-1 activity in CLN3 disease by deleting Casp1 — the gene containing the instructions for the production of caspase-1 — from a mouse model of CLN3 disease.

They found that the deletion of Casp1 significantly reverted the motor coordination deficits and the abnormal activation of astrocytes characteristic of CLN3 disease, to levels comparable to those of healthy mice.

However, not all features of CLN3 disease were found to be influenced by caspase-1, since lysosomal accumulation and microglial activation were similar between CLN3 mice with or without the Casp1 gene.

These results reinforced the idea that lysosomal accumulation is not the main driver of neurodegeneration in CLN3 disease.

Also, while mice with CLN3 disease have shorter whiskers, Casp1 deletion in these mice resulted in longer whiskers, partially rescuing their length to that of healthy mice.

“Based on the importance of whiskers for object identification and navigation, the whisker atrophy in … [mice with CLN3 disease] suggests an intriguing functional parallel with visual loss in CLN3 patients, although this remains highly speculative,” researchers wrote.

“This study is the first to document a pathological role for caspase-1 activity in [mice with CLN3 disease] …, revealing an impact on motor behavior, astrocyte activation, and whisker length,” they added.

The results suggest that targeting caspase-1 in patients with CLN3 disease may potentially revert some of the features/symptoms of the disease.

The team noted that additional studies are necessary to identify caspase-1 target molecules, which may unravel new underlying mechanisms of CLN3 disease.