Wayne State University researcher identifies possible cause for neurodegenerativ

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Wayne State University researcher identifies possible cause for

neurodegenerative Charcot-Marie-Tooth type 4J disorder

October 18, 2010

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. "

Wayne State University is one of the nation's pre-eminent public research

universities in an urban setting. Through its multidisciplinary approach to

research and education, and its ongoing collaboration with government, industry

and other institutions, the university seeks to enhance economic growth and

improve the quality of life in the city of Detroit, state of Michigan and

throughout the world. For more information on research at Wayne State

University, visit http://www.research.wayne.edu.