DETROIT- A Wayne State University researcher has identified a novel regulatory mechanism that may be the cause behind the pathogenesis of Charcot-Marie-Tooth type 4J (CMT4J) disease.

Assia Shisheva, Ph.D., professor of physiology in the School of Medicine and resident of Royal Oak, Mich., was published in the August 27th issue of The Journal of Biological Chemistry for a study that identified a novel mechanism associated with the regulation of intracellular levels of PtdIns(3,5)P2, a signaling lipid critical in neurodegeneration.

CMT4J is a recessively inherited disorder in which patients slowly lose normal use of their feet, legs, hands and arms as nerves to the extremities degenerate and the muscles in the extremities become weakened due to the loss of stimulation by the affected nerves. Many patients also have some loss of sensory nerve function.

A 2007 University of Michigan study published in Nature found that the enzyme that destroys PtdIns(3,5)P2, known as Sac3, is mutated in patients with peripheral neuropathy, hence the CMT4J disorder. This mutation involves a single amino acid substitution at position 41, i.e., Sac3I41T and results in a variation of the protein Sac3, which is present as a single allele - patients are missing the other allele altogether. "With this study, we set out to discover what happens differently because of this mutation, and if this I-to-T amino acid substitution is related to changes in intracellular PtdIns(3,5)P2 regulatory mechanisms," Shisheva said.

The study found that the Sac3's mutant form, Sac3I41T, does not have the ability to sense the presence of ArPIKfyve, a "scaffold" protein that, as Shisheva's lab discovered and reported in the current accelerated publication, exhibits the property to protect normal Sac3 from rapid degradation. Because Sac3I41T is degraded too quickly, optimal synthesis of PtdIns(3,5)P2 cannot occur. "We don't yet know why this is, but we believe this rapid degradation of Sac3I41T may be the cause of CMT4J," Shisheva said.

The current findings are the most recent in a decade-long line of research on the regulation of PtdIns(3,5)P2 metabolism by Shisheva's lab. In that time, they have identified Sac3, ArPIKfyve and PIKfyve, the principle enzyme that makes PtdIns(3,5)P2, as a triple complex of proteins that work interdependently to both activate and destroy PtdIns(3,5)P2, thereby achieving tight regulation of the PtdIns(3,5)P2 levels at the intracellular membranes.

Shisheva said the next step in this line of research is to use cells from patients with CMT4J to verify that the rapid loss of the Sac3 variant is indeed the mechanism behind the pathogenesis of CMT4J. If it is, the focus could then turn to enabling the mutant form of Sac3 to live longer, or through some other yet-to-be determined mechanism.

"This study has built a foundation for a basic understanding of the regulatory mechanism for PtdIns(3,5)P2," Shisheva said. "Now, we will move forward to search for remedies of this mechanism specifically in terms of a potential treatment for CMT4J."

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