Novel autoantibodies against the proteasome subunit PSMA7 in amyotrophic lateral sclerosis

Objective: To identify autoantibodies using sera from ALS patients and elucidate their roles in disease pathology.

Methods: An immunological screening was performed with a phage expression library SEREX method using sera from 3 ALS patients to identify ALS-related autoantibodies. Levels of antibodies identified by SEREX were measured in 33 ALS patients and 30 normal controls (NCs) by AlphaLISA using recombinant non-full-length proteins. The results were then validated by ELISA using full-length proteins in 71 ALS patients, 30 NCs and 34 disease controls (DCs). The relationship between the titres and clinical profiles of ALS patients were examined.

Results: Four autoantibodies identified by SEREX were proteasome subunit alpha type 7 (PSMA7), vimentin, hydroxymethylbilane synthase and TBC1 domain family member 2 (TBC1D2). AlphaLISA revealed that only the anti-PSMA7 and anti-TBC1D2 levels were significantly different between the ALS and NCs groups. ELISA showed that only the levels of antibody against PSMA7, involved in protein degradation by the ubiquitin-proteasome pathway (UPP), were higher in the ALS group than both the NC (P < .01) and DC (P = .034) groups. Anti-PSMA7 levels tended to be negatively correlated with the logarithm of disease duration (P = .052) and were significantly positively correlated with the logarithm of creatine kinase levels (P = .011). The anti-PSMA7 antibody levels were different between patients with and without dysphagia (P < .01).

Conclusions: Serum anti-PSMA7 antibody might be a disease-promoting factor in early-stage ALS and might be a biomarker of ALS. Anti-PSMA7 autoantibody might contribute to the pathogenesis of ALS, possibly via its role in the UPP.