Anavex Life Sciences Corp (AVXL)

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Falconer, you state:

As with fragile-X syndrome, a large number of diseases and conditions are caused by gene expression dysfunction. The genes are in the DNA, in the chromosomes, and often even get properly expressed in younger periods of life. But at various times, for various reasons, the chromatin wrapped around the compressed coils of DNA in the chromosomes fails to fully unwrap, or otherwise interferes with gene expression.

Does this describe a process that could create the failure?

Ciprofloxacin impairs mitochondrial DNA replication initiation through inhibition of Topoisomerase 2

Anu Hangas 1, Koit Aasumets 2, Nina J Kekäläinen 1, Mika Paloheinä 1, Jaakko L Pohjoismäki 1, Joachim M Gerhold 2, Steffi Goffart 1
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PMID: 30169847 PMCID: PMC6182158 DOI: 10.1093/nar/gky793
Free PMC article
Abstract
Maintenance of topological homeostasis is vital for gene expression and genome replication in all organisms. Similar to other circular genomes, also mitochondrial DNA (mtDNA) is known to exist in various different topological forms, although their functional significance remains unknown. We report here that both known type II topoisomerases Top2a and Top2ß are present in mammalian mitochondria, with especially Top2ß regulating the supercoiling state of mtDNA. Loss of Top2ß or its inhibition by ciprofloxacin results in accumulation of positively supercoiled mtDNA, followed by cessation of mitochondrial transcription and replication initiation, causing depletion of mtDNA copy number. These mitochondrial effects block both cell proliferation and differentiation, possibly explaining some of the side effects associated with fluoroquinolone antibiotics. Our results show for the first time the importance of topology for maintenance of mtDNA homeostasis and provide novel insight into the mitochondrial effects of fluoroquinolones.

https://pubmed.ncbi.nlm.nih.gov/30169847/

Int J Mol Sci
. 2019 Apr 25;20(8):2041. doi: 10.3390/ijms20082041.
Twist and Turn-Topoisomerase Functions in Mitochondrial DNA Maintenance
Steffi Goffart 1, Anu Hangas 2, Jaakko L O Pohjoismäki 3
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PMID: 31027213 PMCID: PMC6514783 DOI: 10.3390/ijms20082041
Free PMC article
Abstract
Like any genome, mitochondrial DNA (mtDNA) also requires the action of topoisomerases to resolve topological problems in its maintenance, but for a long time, little was known about mitochondrial topoisomerases. The last years have brought a closer insight into the function of these fascinating enzymes in mtDNA topology regulation, replication, transcription, and segregation. Here, we summarize the current knowledge about mitochondrial topoisomerases, paying special attention to mammalian mitochondrial genome maintenance. We also discuss the open gaps in the existing knowledge of mtDNA topology control and the potential involvement of mitochondrial topoisomerases in human pathologies. While Top1mt, the only exclusively mitochondrial topoisomerase in mammals, has been studied intensively for nearly a decade, only recent studies have shed some light onto the mitochondrial function of Top2ß and Top3a, enzymes that are shared between nucleus and mitochondria. Top3a mediates the segregation of freshly replicated mtDNA molecules, and its dysfunction leads to mtDNA aggregation and copy number depletion in patients. Top2ß, in contrast, regulates mitochondrial DNA replication and transcription through the alteration of mtDNA topology, a fact that should be acknowledged due to the frequent use of Topoisomerase 2 inhibitors in medical therapy.

https://pubmed.ncbi.nlm.nih.gov/31027213/