Abstract Details

Title Curcumin Derivatives Reduce Expression of Transcription Factors That Inhibit Myelination in R98C CMT1B Mouse

Topic Peripheral Nerve

Presentation(s) P05 - (-)

Poster/Presentation
Number 066

Objective

Background BACKGROUND: MPZ mutations such as R98C cause ER retention of the mutant protein and activation of the unfolded protein response (UPR). Curcumin derivative treatment of R98C mice improved their neuropathy by clinical physiological and morphological criteria. UPR activation is reduced in treated mice but the molecular basis for the improvement is not known. Previous studies have demonstrated that the R98C mutation increases expression of c-Jun, a transcription factor that inhibits Schwann cell myelination.

Design/Methods DESIGN/METHODS: R98C mice were treated with phosphatidyl choline curcumin (PCC) or curcumin dissolved in sesame oil (CO) by daily gavage beginning at post natal day 4 and evaluated at multiple time points up to three months of age. Mice were evaluated clinically, by rotarod and grip strength, physiologically by nerve conduction studies and morphologically including analysis of neuromuscular junctions (NMJ). RTPCR, immunohistochemistry and teased fiber IHC were used to analyze expression of transcription factors known to regulate PNS myelination.

Results RESULTS: Treated mice performed better than untreated animals on the rotarod, had increased CMAP amplitudes and increased numbers of large diameter axons. IHC data demonstrated a decrease in Schwann cell c-Jun and SCIP expression; both transcription factors inhibit myelination. RTPCR results demonstrated a reduction in SCIP mRNA levels.Increased myelination of pre-terminal axons at NMJ occurred in treated animals as did decreased XBP-splicing, a marker of UPR activation.

Conclusions CONCLUSIONS: Improvement in R98C mice may result from decreased expression of inhibitory transcription factors increased myelination of pre-terminal axons and reduction of the UPR activation.

Authors/Disclosures
PRESENTER	No disclosure on file
Agnes Patzko, MD	No disclosure on file
Suola Wang	No disclosure on file
Xingyao Wu (Wayne State University)	No disclosure on file
Mario A. Saporta, MD, PhD, FAAN (University of Miami)	Dr. Saporta has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for SwanBio. Dr. Saporta has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Pharnext. Dr. Saporta has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Applied Therapeutics.
	No disclosure on file
Lawrence G. Wrabetz, MD (SUNY Buffalo School of Medicine)	No disclosure on file
Michael E. Shy, MD, FAAN (University of Iowa)	Dr. Shy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Shy has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for DTx Pharma. The institution of Dr. Shy has received research support from NIH. The institution of Dr. Shy has received research support from Muscular Dystrophy Association. The institution of Dr. Shy has received research support from Charcot Marie Tooth Association. The institution of Dr. Shy has received research support from Applied Therapeutics.
	No disclosure on file

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