In a groundbreaking study led by Drs. Bo Hu and Jun Li, neurology researchers at Houston Methodist Hospital have identified a crucial factor influencing nerve myelination and uncovered a promising therapeutic target for millions of individuals living with peripheral nerve disease.

The mouse study, published in the journal Brain, reveals the pivotal role of p21-activated kinase 2 (PAK2) in the process of myelination, particularly in Schwann cells.

Myelination, the process by which nerves are enveloped in a protective sheath of myelin, is vital for efficient nerve conduction and overall nervous system function. Disruptions in myelination can lead to a range of neurological disorders, highlighting the importance of understanding the underlying mechanisms.

Developing a knockout model

To investigate the role of PAK2 in myelination, the research team developed a Schwann cell-specific knockout mouse model that demonstrated significant motor and growth impairment within weeks of birth.

"The deletion of PAK2 in Schwann cells resulted in severe hypomyelination, slowed nerve conduction velocity and behavioral dysfunctions in the peripheral nerves of these mice," said Dr. Hu, an assistant professor of neurology at Houston Methodist. "Many Schwann cells in the affected nerves were found to be arrested at the stage of axonal sorting, emphasizing the critical role of PAK2 in myelin development."

Remarkably, reintroducing PAK2 — but not a kinase-dead mutant of PAK2 — via lentivirus delivery rescued the abnormalities observed in the knockout mice, underscoring the necessity of PAK2 kinase activity for proper myelination.

Additionally, the study revealed that PAK2 acts as a convergence point for multiple promyelinating signaling pathways, responding to signals from molecules such as neuregulin-1 and prion protein.

Therapeutic potential

One of the most intriguing findings of the study is the influence of myelin lipids on PAK2 activity.

"Certain myelin lipids were found to either enhance or inhibit PAK2 activation, suggesting a potential avenue for therapeutic interventions aimed at modulating PAK2 function to repair abnormal myelination in peripheral neuropathies," Dr. Hu noted.

The lipid effect could function as a feedback mechanism to promote or curb myelination, manipulating PAK2 activity via the delivery of specific myelin lipids or even lipid diet modification.

In addition to identifying PAK2 as a novel promyelinating factor, the study examined the complex interplay between PAK2 and various signaling pathways involved in myelination.

The researchers observed a decrease of PAK2 activity in a mouse model of Charcot-Marie-Tooth syndrome, an inherited hypomyelination condition in the nerves that supply feet, legs, hands and arms.

"This discovery opens new avenues for exploring therapeutic strategies targeting PAK2 activity, potentially offering hope for the treatment of neurological disorders associated with disrupted myelination," said Dr. Hu.

A uniquely important role

The significance of PAK2 in myelination was further emphasized by the lack of phenotype observed in mice with ablation of PAK2 in neurons, indicating that the promyelinating effects of PAK2 are Schwann cell-autonomous.

"This means they can carry out vital functions for the health, maintenance and repair of the peripheral nervous system independently," Dr. Hu explained. "For instance, in cases of nerve injury, they can initiate nerve repair and regeneration."

Furthermore, although there is a high homology of amino acid sequence between PAK1 and PAK2, no abnormalities were detected in the researchers' PAK1 knockout model.

"This was a surprising finding, considering the signaling structures are almost identical in the PAK1 and PAK2 complexes," Dr. Hu said. "The mechanism for their differences remains unclear, but what is clear from this research is that promyelination pathways are dependent on PAK2 and not PAK1."

Representing a significant and original contribution toward advancing our understanding of the molecular mechanisms underlying nerve myelination, the research paves the way for future therapeutic interventions aimed at restoring normal myelination in neurological disorders.