Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis
Interdisciplinary Graduate Program
Department of Neurology; Department of Biochemistry and Molecular Pharmacology
Genetics | Genomics | Molecular Biology | Molecular Genetics | Nervous System Diseases | Neurology | Neuroscience and Neurobiology
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.
DOI of Published Version
Nature. 2012 Aug 23;488(7412):499-503. doi: 10.1038/nature11280. Link to article on publisher's site
Wu C, Keagle PJ, Sapp P, Piotrowska K, Lowe P, McKenna-Yasek D, Baron D, Kost JE, Gonzalez-Perez P, Fox AD, Adams J, Leclerc AL, Moore MJ, Zitzewitz JA, Xu Z, Bosco D, Brown RH, Landers JE. (2012). Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. GSBS Student Publications. https://doi.org/10.1038/nature11280. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/1992