Impaired Cu-Zn superoxide dismutase (SOD1) and calcineurin (Cn) interaction in ALS: A presumed consequence for TDP-43 and zinc aggregation in Tg SOD1G93A rodent spinal cord tissue.

Kim, J. M.; Billington, E.; Reyes, A.; Notarianni, T.; Sage, J. M.; Agbas, E.; Taylor, M.; Monast, I.; Stanford, J. A.; Agbas, A.

doi:10.1101/220210

bioRxiv · 10.1101/220210

Impaired Cu-Zn superoxide dismutase (SOD1) and calcineurin (Cn) interaction in ALS: A presumed consequence for TDP-43 and zinc aggregation in Tg SOD1G93A rodent spinal cord tissue.

Kim, J. M.·Billington, E.·Reyes, A.·Notarianni, T.·Sage, J. M.·Agbas, E.·Taylor, M.·Monast, I.·Stanford, J. A.·Agbas, A.

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Abstract

Impaired interactions between Calcineurin (Cn) and (Cu/Zn) superoxide dismutase (SOD1) are suspected to be responsible for the formation of hyperphosphorylated protein aggregation in amyotrophic lateral sclerosis (ALS). Serine (Ser)-enriched TDP-43 protein aggregation appears in the spinal cord of ALS animal models, and may be linked to the reduced phosphatase activity of Cn. The mutant overexpressed SOD1G93A protein does not properly bind zinc (Zn) in animal models; hence, mutant SOD1G93A - Cn interaction weakens. Consequently, unstable Cn fails to dephosphorylate TDP-43 that yields hyperphosphorylated TDP-43 aggregates. Our previous studies had suggested that Cn and SOD1 interaction was necessary to keep Cn enzyme functional. We have observed low Cn level, increased Zn concentrations, and increased TDP-43 protein levels in cervical, thoracic, lumbar, and sacral regions of the spinal cord tissue homogenates. This study further supports our previous published work indicating that Cn stability depends on functional Cn-SOD1 interaction because Zn metal is crucial for maintaining the Cn stability. Less active Cn did not efficiently dephosphorylate TDP-43; hence TDP-43 aggregations appeared in the spinal cord tissue.

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Kim, J. M., Billington, E., Reyes, A., Notarianni, T., Sage, J. M., Agbas, E., Taylor, M., Monast, I., Stanford, J. A., Agbas, A.. 2017-11-15. Impaired Cu-Zn superoxide dismutase (SOD1) and calcineurin (Cn) interaction in ALS: A presumed consequence for TDP-43 and zinc aggregation in Tg SOD1G93A rodent spinal cord tissue.. https://doi.org/10.1101/220210

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