We propose that amyotrophic lateral sclerosis patients and family members with high serum isoleucine levels should be offered supplementation with vitamin B12. Multivariable Mendelian randomization revealed that the toxic effect of isoleucine is dependent on the depletion of vitamin B12 consistent with this, rare variants which reduce the function of MMUT are protective against amyotrophic lateral sclerosis. Isoleucine is metabolized via methylmalonyl-CoA mutase encoded by the gene MMUT in a reaction that consumes vitamin B12. Finally, in a zebrafish model of C9ORF72-amyotrophic lateral sclerosis, we present evidence that estradiol is neuroprotective.
Estrone-3-sulphate is metabolized to the more active estradiol by the enzyme 17β-hydroxysteroid dehydrogenase 1 further, Mendelian randomization demonstrated a protective effect of estradiol and rare variant analysis showed that missense variants within HSD17B1, the gene encoding 17β-hydroxysteroid dehydrogenase 1, modify risk for amyotrophic lateral sclerosis. All three metabolites were supported by robust Mendelian randomization measures and sensitivity analyses estrone-3-sulphate and isoleucine were confirmed in a validation amyotrophic lateral sclerosis genome-wide association study. Serum isoleucine was positively associated with amyotrophic lateral sclerosis risk. After stringent Bonferroni multiple testing correction, our unbiased screen revealed three metabolites that were significantly linked to the risk of amyotrophic lateral sclerosis: Estrone-3-sulphate and bradykinin were protective, which is consistent with literature describing a male preponderance of amyotrophic lateral sclerosis and a preventive effect of angiotensin-converting enzyme inhibitors which inhibit the breakdown of bradykinin. For each metabolite, we performed Mendelian randomization using an inverse variance weighted estimate for significance testing. We obtained genome-wide association study summary statistics for serum concentrations of 566 metabolites which were population matched with a genome-wide association study of amyotrophic lateral sclerosis. Two-sample Mendelian randomization enables causal inference between an exposure, such as the serum concentration of a specific metabolite, and disease risk.
The cause of amyotrophic lateral sclerosis is unknown in the majority of cases. It was the beginning of the end.Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects 1/350 individuals in the United Kingdom. Two years before this, its beautiful neon signage was taken down, and replaced by a considerably less inspiring ‘IMC’ branding. Like many, I was sad but not surprised when its closure was announced in February of last year. Among other films, I watched the Leonard Cohen documentary I’m Your Man there, almost having the entire place to myself (maybe such solitary film screenings were part of the problem!). With its focus on independent and foreign films, the Screen certainly built a cult following around itself. Screen stood outside of the Screen Cinema (originally The New Metropole) on the corner of Hawkins Street and Townsend Street. Screen earlier this week, while making my way along Tara Street:
Many of the boxes have touched on local history and folklore, ranging from the United Irishmen of the 1790s to Dublin street characters. Particular favourites include ‘Bo’ by Áine Macken (fittingly enough right beside Dublin’s historic Cowtown), Sarah Macken’s gorgeous tribute to Oscar Wilde, and Sheila Flaherty’s ‘Art Inspires The World’. To date, dozens of boxes have been painted right across the city, bringing a touch of colour to these rather boring features of the urban landscape. Since 2013, DCC have experimented with an art programme involving the traffic light control boxes of the city. One of my favourite things in the city in recent years has been the Dublin Canvas project, which is funded and supported by Dublin City Council.
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