Isoform-specific expression and ratio changes accompany oxidant-induced peripherin aggregation in a neuroblastoma...

The type III intermediate filament peripherin is found associated with pathological inclusions present within motor neurons of patients with amyotrophic lateral sclerosis (ALS). Peripherin intra-isoform associations contribute to filament network formation at defined stoichiometric ratios. Distinct biochemical signatures characterize peripherin isoform expression in traumatic neuronal injury and motor neuron disease, while disruptions to peripherin alternative splicing or translation are associated with inclusion formation. In our efforts to identify pathological relationships between peripherin isoform expression and inclusion formation, we provide evidence of peripherin isoform-specific expression and ratio changes with concomitant, dose-dependent inclusion formation in response to oxidative stress. Upon increasing exposure to physiologically relevant levels of hydrogen peroxide in Neuro-2a cells, we observed a significant increase and decrease in peripherin isoforms Per-58 and Per-45, respectively, with peripherin-specific perikaryal aggregation of filaments 10-15 μm in diameter. Interestingly, peripherin-immunoreactive inclusions showed no overt carbonylation, suggesting that aggregation may serve a physiologically relevant role during oxidative stress. These findings provide novel insight into the biological significance of peripherin isoforms and inclusion formation, with relevance to the pathology of ALS.