期刊
JOURNAL OF NEUROSCIENCE
卷 27, 期 36, 页码 9801-9815出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2661-07.2007
关键词
protein aggregation disease; amyotrophic lateral sclerosis; ALS; endoplasmic reticulum; lipid-binding protein; VAP family proteins; motor neuron disease
The vesicle- associated membrane protein- associated proteins ( VAPs) VAPA and VAPB interact with lipid- binding proteins carrying a short motif containing two phenylalanines in an acidic tract ( FFAT motif) and targets them to the cytosolic surface of the endoplasmic reticulum ( ER). A genetic mutation ( P56S) in the conserved major sperm protein homology domain of VAPB has been linked to motor-neuron degeneration in affected amyotrophic lateral sclerosis ( ALS) patients. We report that in the CNS, VAPB is abundant in motor neurons and that the P56S substitution causes aggregation of mutant VAPB in immobile tubular ER clusters, perturbs FFAT- motif binding, and traps endogenous VAP in mutant aggregates. Expression of mutant VAPB or reduction of VAP by short hairpin RNA in primary neurons causes Golgi dispersion and cell death. VAPA and VAPB are reduced in human ALS patients and superoxide dismutase 1 ( SOD1)-ALS- transgenic mice, suggesting that VAP family proteins may be involved in the pathogenesis of sporadic and SOD1- linked ALS. Our data support a model in which reduced levels of VAP family proteins result in decreased ER anchoring of lipid- binding proteins and cause motor neuron degeneration.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据