期刊
NATURE
卷 488, 期 7412, 页码 499-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11280
关键词
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资金
- ALS Therapy Alliance
- Project ALS
- P2ALS
- Angel Fund
- Pierre L. de Bourgknecht ALS Research Foundation
- Al-Athel ALS Research Foundation
- ALS Family Charitable Foundation
- National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) [1R01NS065847, 1R01NS050557, RC2-NS070-342]
- Muscular Dystrophy Association [MDA173851]
- Ministry of Health
- SMA Europe fellowship
- Massachusetts Institute of Technology
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years(1-9), nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.
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