New evidence that α-synuclein (α-syn) can contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS) has come from an analysis of cerebrospinal fluid from 127 people with ALS. Use of an α-syn seed amplification assay identified toxic forms of the protein in 18 people with familial, sporadic or Guamanian forms of ALS. The findings suggest that α-syn aggregation, which is most commonly associated with Parkinson disease, contributes to pathogenesis in a subset of cases of ALS, with implications for diagnosis and treatment.