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New Research Links miR-128 with Motor Hyperactivity, Epilepsy

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A team led by researchers from Mount Sinai this week reported the discovery that a single microRNA — miR-128 — plays a major role in nerve cell excitability and motor activity by regulating an entire neuronal signaling pathway.

The data, which were generated in mice, also show that inhibition of the miRNA triggered increased motor activity and fatal epilepsy, and that its overexpression attenuated neural responsiveness, suppressed motor activity, and alleviated the movement abnormalities associated with Parkinson's-like disease and seizures.

Taken together, the findings indicate that miR-128 may be a therapeutic target for epilepsy and other movement disorders, according to Mount Sinai researcher and study author Anne Schaefer.

To date, there has been significant research into the roles of miRNAs in neural cells, including studies from the lab of Stanford University's Jerry Crabtree, who showed in 2011 that expression of two miRNAs in human fibroblasts induces the cells conversion into neurons.

This and other work has established the importance of the miRNA mechanism to the nervous system. But until now, there has not been evidence that changes in expression of a single miRNA could impact complex neurological behaviors, Schaefer noted.

In 2007, she and colleagues at Rockefeller University showed through Dicer ablation studies that miRNAs are required for the survival of differentiated neurons. Then, in 2010, they reported data showing that a deficiency of Argonaute 2 in the neurons of mice alleviated cocaine addiction, which was associated with selective downregulation of certain miRNAs in the animals' striata.

"The mice fail to self-administer cocaine, meaning that these neurons are not able to respond appropriate to their inputs," she told Gene Silencing News this week. Taken together, the data from the two papers demonstrated that "microRNAs are important for maintaining normal adult neural survival and function."

Aiming to determine if there are individual miRNAs with particularly important functions in the brain, Schaefer — now at Mount Sinai — started hunting down likely candidates, focusing on miRNAs that are induced postnatally and are neuron-specific, are expressed at high levels, and are conserved in humans.

Reviews of the literature and in vitro screening led her and her team to miR-128.

Notably, the miRNA is encoded by two separate genes — miR-128-1 and miR-128-2 on mouse chromosomes 1 and 9, or human chromosomes 2 and 3, respectively. Although the investigators suspected that the two genes might act in a compensatory manner with regards to the miRNA, knockout experiments showed that it was miR-128-2 that was predominately responsible for the miRNA, according to their study, which appeared in Science.

Along with a reduction in mature miR-128, mice lacking the miR-128-2 gene also experienced hyperactivity and increased exploration by four weeks of age, which progressed quickly to severe seizures and death at two to three months of age. Importantly, the lethal impact of miR-128 downregulation could be prevented by treatment with an anticonvulsive drug, indicating the causal role of seizures in the animals' deaths.

The team was also able to normalize the animals' motor activity and prevent seizures by ectopically expressing miRNA-128 in their neurons, and determined that the miRNA regulated motor activity by "suppressing the expression of various ion channels and signaling components of the extracellular signal-regulated kinase ERK2 network that regulate neuronal excitability," they wrote in their paper.

Further experiments showed that miR-128 deficiency in the striatal neurons mimics the hypersensitivity of the nerve cells in mice suffering from Parkinson's-like syndrome. Conversely, overexpression of the miRNA in neurons was associated with a reduction in ERK2 activation and decreased motor activity in mice, and protected the animals from the abnormal behavior triggered by chemically induced Parkinson's disease.

"The human miR-128-2 gene on chromosome 3p lies within a region that has been linked to idiopathic generalized epilepsy," the researchers concluded in their paper. "It is tempting to speculate that changes in miR-128 or miR-128 target gene expression could be a potential cause of increased neuronal excitability and epilepsy in humans."

If this is the case, Schaefer said, "one could [potentially] use miR-128 overexpression in specific neurons and specific brain regions to suppress seizure susceptibility in severe cases of epilepsy."

This therapeutic approach, however, will require further study, she added, noting that experiments are underway in her lab to see if, among other things, epilepsy patients have abnormal expression of miR-128.

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