期刊
ASN NEURO
卷 1, 期 3, 页码 -出版社
SAGE PUBLICATIONS LTD
DOI: 10.1042/AN20090028
关键词
mitochondrion; oligodendrocyte; oxidative phosphorylation; Pelizaeus-Merzbacher disease; Plp1 mutant
资金
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke [NS38236]
- European Leukodystrophy Association [ELA 2006-055C5]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS038236] Funding Source: NIH RePORTER
PMD (Pelizaeus-Merzbacher disease), a CNS (central nervous system) disease characterized by shortened life-span 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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