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

Background Alpha-synuclein (alpha-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 alpha-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 alpha-Syn can be identified in spinal fluid of patients with ALS including familial, sporadic, and Guamanian forms of the disease. Methods Based on the finding that alpha-Syn has been found to be a prion-like protein, we have utilized a validated alpha-Synuclein seed amplification assay to determine if seed-competent alpha-Syn could be detected in the spinal fluid of patients with ALS. Results Toxic species of alpha-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. Conclusions Our findings suggest that a sub-group of ALS occurs in which self-replicating alpha-Syn is detectable and likely contributes to its pathogenesis. This finding may have implications for the diagnosis and treatment of this disorder.