Curcumin treatment abrogates endoplasmic reticulum retention and aggregation-induced apoptosis associated with neuropathy-causing myelin protein zero-truncating mutants

Mehrdad Khajavi, Ken Inoue, Wojciech Wiszniewski, Tomoko Ohyama, G. Jackson Snipes, James R. Lupski

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

Mutations in MPZ, the gene encoding myelin protein zero (MPZ), the major protein constituent of peripheral myelin, can cause the adult-onset, inherited neuropathy Charcot-Marie-Tooth disease, as well as the more severe, childhood-onset Bejerine-Sottas neuropathy and congenital hypomyelinating neuropathy. Most MPZ-truncating mutations associated with severe forms of peripheral neuropathy result in premature termination codons within the terminal or penultimate exons that are not subject to nonsense-mediated decay and are stably translated into mutant proteins with potential dominant-negative activity. However, some truncating mutations at the 3′ end of MPZ escape the nonsense-mediated decay pathway and cause a mild peripheral neuropathy phenotype. We examined the functional properties of MPZ-truncating proteins that escaped nonsense-mediated decay, and we found that frameshift mutations associated with severe disease cause an intracellular accumulation of mutant proteins, primarily within the endoplasmic reticulum (ER), which induces apoptosis. Curcumin, a chemical compound derived from the curry spice tumeric, releases the ER-retained MPZ mutants into the cytoplasm accompanied by a lower number of apoptotic cells. Our findings suggest that curcumin treatment is sufficient to relieve the toxic effect of mutant aggregation-induced apoptosis and may potentially have a therapeutic role in treating selected forms of inherited peripheral neuropathies.

Original languageEnglish (US)
Pages (from-to)841-850
Number of pages10
JournalAmerican Journal of Human Genetics
Volume77
Issue number5
DOIs
StatePublished - Nov 2005
Externally publishedYes

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Myelin P0 Protein
Curcumin
Endoplasmic Reticulum
Apoptosis
Peripheral Nervous System Diseases
Mutant Proteins
Mutation
Charcot-Marie-Tooth Disease
Curcuma
Spices
Frameshift Mutation
Nonsense Codon
Poisons
Myelin Sheath
Exons
Cytoplasm
Proteins
Cell Count
Phenotype
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Curcumin treatment abrogates endoplasmic reticulum retention and aggregation-induced apoptosis associated with neuropathy-causing myelin protein zero-truncating mutants. / Khajavi, Mehrdad; Inoue, Ken; Wiszniewski, Wojciech; Ohyama, Tomoko; Snipes, G. Jackson; Lupski, James R.

In: American Journal of Human Genetics, Vol. 77, No. 5, 11.2005, p. 841-850.

Research output: Contribution to journalArticle

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