Misfolded alpha‐synuclein in amyotrophic lateral sclerosis: Implications for diagnosis and treatment

Abstract

BackgroundAlpha‐synuclein (α‐Syn) oligomers and fibrils have been shown to augment the aggregation of TAR DNA‐binding Protein 43 (TDP‐43) monomers in vitro, supporting the idea that TDP‐43 proteinopathies such as ALS may be modulated by the presence of toxic forms of α‐Syn 1. Recently, parkinsonian features were reported in a study of European patients 2 and Lewy bodies have been demonstrated pathologically in a similar series of patients 3. Based on these and other considerations, we sought to determine whether seed‐competent α‐Syn can be identified in spinal fluid of patients with ALS including familial, sporadic, and Guamanian forms of the disease.MethodsBased on the finding that α‐Syn has been found to be a prion‐like protein, we have utilized a validated α‐Synuclein seed amplification assay to determine if seed‐competent α‐Syn could be detected in the spinal fluid of patients with ALS.ResultsToxic species of α‐Syn were detected in CSF in 18 of 127 ALS patients, 5 of whom were from Guam. Two out of twenty six samples from patients with C9orf72 variant ALS had positive seed‐amplification assay (SAAs). No positive tests were noted in superoxide dismutase type 1 ALS subjects (n = 14). The SAA was negative in 31 control subjects.ConclusionsOur findings suggest that a sub‐group of ALS occurs in which self‐replicating α‐Syn is detectable and likely contributes to its pathogenesis. This finding may have implications for the diagnosis and treatment of this disorder.