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, 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.
|Autori:||Wu CH; Fallini C; Ticozzi N; Keagle PJ; Sapp PC; Piotrowska K; Lowe P; Koppers M; McKenna-Yasek D; Baron DM; Kost JE; Gonzalez-Perez P; Fox AD; Adams J; Taroni F; Tiloca C; Leclerc AL; Chafe SC; Mangroo D; Moore MJ; Zitzewitz JA; Xu ZS; van den Berg LH; Glass JD; Siciliano G; Cirulli ET; Goldstein DB; Salachas F; Meininger V; Rossoll W; Ratti A; Gellera C; Bosco DA; Bassell GJ; Silani V; Drory VE; Brown RH; Landers JE|
|Titolo:||Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis|
|Anno del prodotto:||2012|
|Digital Object Identifier (DOI):||10.1038/nature11280|
|Appare nelle tipologie:||1.1 Articolo in rivista|