期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 16, 页码 7556-7561出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0914128107
关键词
motor neuron disease; neurodegeneration; linkage analysis; ubiquitinated aggregates; apoptosis
资金
- Smith's Charity
- American ALS Association
- Haywood Foundation
- Motor Neurone Disease Association
- Garfield Weston Foundation
- Land Securities Group
- Medical Research Council [G0701159] Funding Source: researchfish
- MRC [G0701159] Funding Source: UKRI
We report a unique mutation in the D-amino acid oxidase gene (R199W DAO) associated with classical adult onset familial amyotrophic lateral sclerosis (FALS) in a three generational FALS kindred, after candidate gene screening in a 14.52 cM region on chromosome 12q22-23 linked to disease. Neuronal cell lines expressing R199W DAO showed decreased viability and increased ubiquitinated aggregates compared with cells expressing the wild-type protein. Similarly, lentiviral-mediated expression of R199W DAO in primary motor neuron cultures caused increased TUNEL labeling. This effect was also observed when motor neurons were cocultured on transduced astrocytes expressing R199W, indicating that the motor neuron cell death induced by this mutation is mediated by both cell autonomous and noncell autonomous processes. DAO controls the level of D-serine, which accumulates in the spinal cord in cases of sporadic ALS and in a mouse model of ALS, indicating that this abnormality may represent a fundamental component of ALS pathogenesis.
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