Studies of mice expressing the human C9orf72 gene show that intranasal administration of rifampicin significantly inhibits the formation of RNA foci, DPR inclusions, and TDP-43, thereby improving cognitive function in mice. Credit: Osaka Metropolitan University

What did Stephen Hawking and Mao Zedong have in common? They both suffered from amyotrophic lateral sclerosis (ALS), the treatment of which remains elusive. Researchers from Osaka Metropolitan University have taken an important step towards preventing ALS and another brain disorder called frontotemporal dementia (FTD) by conducting a study of the effects of the antibiotic rifampicin on genetically modified mice. Their paper is published in Biomedicines.

“The main cause of FTD and ALS is the expansion of hexanucleotide repeats (HRE) in non-coding regions of the C9orf72 gene,” said lead researcher Professor Takami Tomiyama. This mutation causes neurodegeneration through loss of function or enhancement of toxic functions. “A mutation in the loss of function is indicated by the formation of a nucleic acid structure called the G-quadruplex that blocks C9orf72 transcription. The mutation in toxic function enhancement is indicated by the formation of RNA foci, toxic RNA aggregates, and dipeptide repeat proteins (DPRs), ”explained Professor Tamiyama. Together, G-quadruplex and DPR further accelerate the aggregation of RNA-binding proteins such as T neurodegeneration.

Rifampicin – an antibiotic that slows down the production of bacterial RNA; it is usually administered in combination with other antibiotics. Investigating the effect of rifampicin on the formation of foci of RNA, DPR, and TDP-43 inclusions, the research team identified its potential to prevent FTD and ALS. They nasally administered rifampicin to mice with the human C9orf72 gene containing 500 hexanucleotide repeat repeats. The team then assessed the cognitive functions of the mice by observing their ability to emerge from the maze before examining their brain tissue.

Cessation of C9orf72-related dementia in mutant mice with the antibiotic rifampicin

Rifampicin treatment significantly improves the cognitive function and memory of C9orf72-transgenic mice. Credit: Osaka Metropolitan University

The results show that intranasal rifampicin treatment significantly improved cognitive function and memory in mice. It significantly inhibits the formation of cytoplasmic inclusions consisting of protein aggregates in brain tissue. Rifampicin also attenuated the formation of RNA foci containing G-quadruplex, although it is unclear how. In addition, synapse loss, neuronal loss, and microglia activation were also attenuated by rifampicin treatment.

This study is the latest in a series of research papers on the effects of rifampicin on the prevention of neurological disorders. “Earlier we showed on model mice that nasal administration rifampicin is effective against dementia such as Alzheimer’s disease, tau-associated FTD and dementia with Levy’s bodies, “concluded Professor Tamiyama. of the C9orf72 gene. Rifampicin may be a widely effective drug for the prevention of neurodegenerative diseases.”

Cessation of nasal dementia with a combination of rifampicin and resveratrol

Additional information:
Yukari Khatanaka et al., Neuropathology associated with re-expansion of hexanucleotide C9orf72, is attenuated by nasal rifampicin in mice, Biomedicines (2022). DOI: 10.3390 / biomedicines10051080

Provided by the capital’s Osaka University

Citation: Cessation of C9orf72-linked dementia in mutant mice with the antibiotic rifampicin (2022, May 23) obtained May 23, 2022 from -mice-antibiotic.html

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