Different proteolipid protein mutants exhibit unique metabolic defects

ASN Neuro
Maik HüttemannRobert P Skoff

Abstract

PMD (Pelizaeus-Merzbacher disease), a CNS (central nervous system) disease characterized by shortened lifespan and severe neural dysfunction, is caused by mutations of the PLP1 (X-linked myelin proteolipid protein) gene. The majority of human PLP1 mutations are caused by duplications; almost all others are caused by missense mutations. The cellular events leading to the phenotype are unknown. The same mutations in non-humans make them ideal models to study the mechanisms that cause neurological sequelae. In the present study we show that mice with Plp1 duplications (Plp1tg) have major mitochondrial deficits with a 50% reduction in ATP, a drastically reduced mitochondrial membrane potential and increased numbers of mitochondria. In contrast, the jp (jimpy) mouse with a Plp1 missense mutation exhibits normal mitochondrial function. We show that PLP in the Plp1tg mice and in Plp1-transfected cells is targeted to mitochondria. PLP has motifs permissive for insertion into mitochondria and deletions near its N-terminus prevent its co-localization to mitochondria. These novel data show that Plp1 missense mutations and duplications of the native Plp1 gene initiate uniquely different cellular responses.

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Citations

May 29, 2014·FEBS Letters·Anna Magdalena SokolAgnieszka Chacinska
Dec 3, 2014·Pulmonary Pharmacology & Therapeutics·Elena RodriguezThomas H Shaffer
Aug 8, 2014·Biochemistry. Biokhimii︠a︡·Yu L BaburinaT S Azarashvili

Methods Mentioned

BETA
PCR
protein assay
transfections
transfection
electron microscopy
electron
transgenic

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