Carbonic Anhydrase I modifies SOD1-induced motor neuron toxicity in Drosophila via ER stress pathway

Abstract

Background: Drosophila models of amyotrophic lateral sclerosis (ALS) have been widely used in understanding molecular mechanisms of ALS pathogenesis as well as discovering potential targets for therapeutic drugs. Mutations in the copper/zinc superoxide dismutase (SOD1) cause ALS by gain of toxic functions and induce toxicity in fl y motor neurons. Results: In this study, we have determined that human carbonic anhydrase I (CA1) can alleviate mutant SOD1-induced motor neuron toxicity in the transgenic fl y model of ALS. Interestingly, we found that motor neuron expression of CA1 could independently induce locomotion defect as well as decreasing the survival rate. In addition, CA1-induced toxicity in motor neurons is anhydrase activity-dependent. Mechanistically, we identifi ed that both SOD1-and CA1-induced toxicity involve the activation of eIF2 in the ER stress response pathway. Downstream activation of the JNK pathway has also been implicated in the induced toxicity. Conclusion: Our results have confi rmed that SOD1-induced toxicity in fl y motor neuron also involves endoplasmic reticulum (ER) stress pathway. More importantly, we have discovered a new cellular role that CA1 plays by antagonizing mutant SOD1-induced toxicity in motor neurons involving the ER stress pathway. Such information can be potentially useful for further understanding disease mechanisms and developing therapeutic targets for ALS. Carbonic Anhydrase I modifi es SOD1-induced motor neuron toxicity in Drosophila via ER stress pathway

Genomic and multi-tissue proteomic integration for understanding the biology of disease and other complex traits

“…Our genetic analyses found a strong pQTL for carbonic anhydrase IV, which is a target for Acetazolamide. Several studies have reported that the expression of Carbonic Anhydrase IV is altered in the motor neurons of Amyotrophic lateral sclerosis patients 42,43 . Acetazolamide is a carbonic anhydrase inhibitor 44 , used to treat glaucoma, epilepsy and altitude sickness 45 .…”

Genomic and multi-tissue proteomic integration for understanding the biology of disease and other complex traits

“…Our genetic analyses found a strong pQTL for carbonic anhydrase IV, which is a target for Acetazolamide. Several studies have reported that the expression of Carbonic Anhydrase IV is altered in the motor neurons of Amyotrophic lateral sclerosis patients 48,49 . Acetazolamide is a carbonic anhydrase inhibitor 50 , used to treat glaucoma, epilepsy and altitude sickness 51 .…”