Expression of Carbonic Anhydrase I in Motor Neurons and Alterations in ALS

Liu, Xiaochen; Lu, Deyi; Bowser, Robert; Liu, Jian

doi:10.3390/ijms17111820

Cited by 22 publications

(17 citation statements)

References 57 publications

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“…Our study for the irst time characterized a novel ly model of motor neuron toxicity that might be relevant to ALS. Previously discovered human CA1 whose levels were shown to be increased in the spinal cord of ALS patients [4], has now been demonstrated that when overexpressed in ly motor neurons is also toxic (Figure 2a & 2d). Among the established Drosophila models of ALS-linked genes, 5 molecules including SOD1, TDP-43, FUS and PFN1, when their wild-type human proteins were overexpressed in ly neurons caused toxicity [31,32,24].…”

Section: Conclusion and Discussionmentioning

confidence: 89%

“…The mechanisms of ALS pathogenesis are complex involving many players and pathways [3]. Recently, it was reported that human carbonic anhydrase I (hCA1) might be a player in ALS pathology as its levels were increased in spinal cord motor neurons of ALS patients including SALS and FALS [4]. Carbonic anhydrases (CAs) catalyze the reversible conversion from carbon dioxide and water to bicarbonate and proton which is the most essential and fundamental process in cellular metabolisms [5].…”

Section: Introductionmentioning

confidence: 99%

“…CA1 is known to be one of the cytosolic isoforms of 17 mammalian CAs which are present in several subcellular compartments [5]. In addition to its expression in erythrocytes, several types of epithelial cells, synovium, and cardiac capillary endothelial cells, CA1 expression was also detected in the motor neurons of human spinal cord [4]. In Drosophila, there are two forms of CAs, CAH1 and CAH2 [7].…”

Section: Introductionmentioning

confidence: 99%

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

Lu¹,

Peng²,

Jia³

et al. 2019

J Neurosci Neurol Disord

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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

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Section: Conclusion and Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Lu¹,

Peng²,

Jia³

et al. 2019

J Neurosci Neurol Disord

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“…Amino alcohols 1–16 were here assayed for their activating properties of 4 catalytically active and physiologically relevant hCA isoforms expressed in human brain, that are: the cytosolic hCA I, II, and VII, and the membrane associated hCA IV 58 . In the CNS context, hCA I is expressed in the motor neurons in human spinal cord 59 . The physiologically dominant isoform hCA II is located both in the choroid plexus, and in oligodendrocytes, myelinated tracts, astrocytes and myelin sheaths in the vertebrates brain 60 .…”

Section: Resultsmentioning

confidence: 99%

Activation of carbonic anhydrases from human brain by amino alcohol oxime ethers: towards human carbonic anhydrase VII selective activators

Nocentini

Cuffaro

Ciccone

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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The synthesis and carbonic anhydrase (CA; EC 4.2.1.1) activating effects of a series of oxime ether-based amino alcohols towards four human (h) CA isoforms expressed in human brain, hCA I, II, IV and VII, are described. Most investigated amino alcohol derivatives induced a consistent activation of the tested CAs, with K A s spanning from a low micromolar to a medium nanomolar range. Specifically, hCA II and VII, putative main CA targets when central nervous system (CNS) diseases are concerned, were most efficiently activated by these oxime ether derivatives. Furthermore, a multitude of selective hCA VII activators were identified. As hCA VII is one of the key isoforms involved in brain metabolism and other brain functions, the identified potent and selective hCA VII activators may be considered of interest for investigations of various therapeutic applications or as lead compounds in search of even more potent and selective CA activators.

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“…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 .…”

Section: Mendelian Randomization To Identify Novel Biomarkers and Drumentioning

confidence: 99%

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

Cruchaga¹,

Yang²,

Farias³

et al. 2020

Preprint

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Understanding the tissue-specific genetic architecture of protein levels is instrumental to understand the biology of health and disease. We generated a genomic atlas of protein levels in multiple neurologically relevant tissues (380 brain, 835 cerebrospinal fluid (CSF) and 529 plasma), by profiling thousands of proteins (713 CSF, 931 plasma and 1079 brain) in a large and well-characterized cohort. We identified 274, 127 and 32 protein quantitative loci (pQTL) for CSF, plasma and brain respectively. cis-pQTL were more likely to be shared across tissues but trans-pQTL tend to be tissue-specific. Between 44% to 68.2% of the pQTL do not colocalize with expression, splicing, methylation or histone QTLs, indicating that protein levels have a different genetic architecture to those that regulate gene expression. By combining our pQTL with Mendelian Randomization approaches we identified potential novel biomarkers and drug targets for neurodegenerative diseases including Alzheimer disease and frontotemporal dementia. Here we present the first multi-tissue study yielding hundred of novel pQTLs. This data will be instrumental to identify the functional gene from GWAS signals, identify novel biological protein-protein interactions, identify novel potential biomarkers and drug targets for complex traits.

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Expression of Carbonic Anhydrase I in Motor Neurons and Alterations in ALS

Cited by 22 publications

References 57 publications

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

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

Activation of carbonic anhydrases from human brain by amino alcohol oxime ethers: towards human carbonic anhydrase VII selective activators

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

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