Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase

被引：183

作者：

Mitchell, John ^{[1
]}

Paul, Praveen ^{[1
]}

Chen, Han-Jou ^{[1
]}

Morris, Alex ^{[1
]}

Payling, Miles ^{[1
]}

Falchi, Mario ^{[2
]}

Habgood, James ^{[1
]}

Panoutsou, Stefania ^{[3
]}

Winkler, Sabine ^{[3
]}

Tisato, Veronica ^{[3
]}

Hajitou, Amin ^{[3
]}

Smith, Bradley ^{[4
,5
]}

Vance, Caroline ^{[4
,5
]}

Shaw, Christopher ^{[4
,5
]}

Mazarakis, Nicholas D. ^{[3
]}

de Belleroche, Jacqueline ^{[1
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Neurogenet Grp, Dept Cellular & Mol Neurosci, Div Neurosci & Mental Hlth, London W12 0NN, England

[2] Univ London Imperial Coll Sci Technol & Med, Sect Genom Med, Fac Med, London W12 0NN, England

[3] Univ London Imperial Coll Sci Technol & Med, Dept Gene Therapy, Div Med, Fac Med, London W2 1PG, England

[4] Kings Coll London, Dept Clin Neurosci, London SE5 8AF, England

[5] Inst Psychiat, London SE5 8AF, England

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2010年 / 107卷 / 16期

关键词：

motor neuron disease; neurodegeneration; linkage analysis; ubiquitinated aggregates; apoptosis; FRONTOTEMPORAL DEMENTIA; SERINE RACEMASE; MOTOR-NEURONS; LENTIVIRAL VECTORS; GENE; ALS; PROTEIN; LOCUS; NEUROTRANSMISSION; MICROGLIA;

D O I：

10.1073/pnas.0914128107

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：7556 / 7561

页数：6

共 32 条

[1] Behavioral and biochemical characterization of a mutant mouse strain lacking D-amino acid oxidase activity and its implications for schizophrenia [J].