Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

Article

关键词: HEXANUCLEOTIDE REPEAT;    SPASTIC PARAPLEGIA;    NEURITE OUTGROWTH;    MUTANT SOD1;    PROTEIN;    ACTIN;    ALS;    C9ORF72;    EXPANSION;    INCREASE;   

DOI  :  10.1038/nature11280

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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