title: Different proteolipid protein mutants exhibit unique metabolic defects.
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.
authors: *Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors: Maik
authors: M
authors: Hüttemann
authors: Zhan
authors: Z
authors: Zhang
authors: Chadwick
authors: C
authors: Mullins
authors: Denise
authors: D
authors: Bessert
authors: Icksoo
authors: I
authors: Lee
authors: Klaus-Armin
authors: KA
authors: Nave
authors: Sunita
authors: S
authors: Appikatla
authors: Robert P
authors: RP
authors: Skoff