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Salk scientists pinpoint key player in Parkinson's disease neuron loss

disease neuron loss

The Salk researchers found that a common genetic mutation involved in Parkinson's disease deforms the membranes (green) surrounding the nuclei (blue) of neural stem cells. The discovery may lead to new ways to diagnose and treat the disease.

By reprogramming skin cells from Parkinson's disease patients with a known genetic mutation, Salk researchers have identified damage to neural stem cells as a powerful player in the disease. The findings, reported in Nature, may lead to new ways to diagnose and treat the disease.

The scientists found that a common mutation to a gene that produces the enzyme LRRK2, which is responsible for both familial and sporadic cases of Parkinson's disease, deforms the membrane surrounding the nucleus of a neural stem cell. Damaging the nuclear architecture leads to destruction of these powerful cells and decreases their ability to spawn functional neurons, such as the ones that respond to dopamine.

The researchers checked their laboratory findings with brain samples from Parkinson's disease patients and found the same nuclear envelope impairment.

"This discovery helps explain how Parkinson's disease, which has been traditionally associated with loss of neurons that produce dopamine and subsequent motor impairment, could lead to locomotor dysfunction and other common non-motor manifestations, such as depression and anxiety," says Juan Carlos Izpisua Belmonte, a professor in Salk's Gene Expression Laboratory, who led the research team. "Similarly, current clinical trials explore the possibility of neural stem cell transplantation to compensate for dopamine deficits. Our work provides the platform for similar trials by using patient-specific corrected cells. It identifies degeneration of the nucleus as a previously unknown player in Parkinson's."

Although the researchers say that they don't yet know whether these nuclear aberrations cause Parkinson's disease or are a consequence of it, they say the discovery could offer clues about potential new therapeutic approaches.

For example, they were able to use targeted gene-editing technologies to correct the mutation in patients' nuclear stem cells. This genetic correction repaired the disorganization of the nuclear envelope and improved overall survival and functioning of the neural stem cells. They were also able to chemically inhibit damage to the nucleus, producing the same results seen with genetic correction. "This opens the door for drug treatment of Parkinson's disease patients who have this genetic mutation," says Izpisua Belmonte.

The new finding may also help clinicians make better diagnoses. "Due to the striking appearance in patient samples," Izpisua Belmonte says, "nuclear deformation parameters could add to the pool of diagnostic features for Parkinson's disease."