Amyotrophic lateral sclerosis (ALS) is a relatively common and rapidly progressive neurodegenerative disease which, in the majority of cases, is thought to be determined by a complex gene-environment interaction. Exponential growth in the number of performed genome-wide association studies (GWAS), combined with the advent of Mendelian randomization (MR) is opening significant new opportunities to identify environmental exposures which increase or decrease the risk of ALS. Each of these discoveries has the potential to shape new therapeutic interventions. However, to do so rigorous methodological standards must be applied in the performance of MR. We have performed a review of MR studies performed in ALS to date. We identified 20 MR studies, including evaluation of physical exercise, adiposity, cognitive performance, immune function, blood lipids, sleep behaviours, educational attainment, alcohol consumption, smoking and type 2 diabetes mellitus. We have evaluated each study using gold standard methodology supported by the MR literature and the STROBE-MR checklist. Where discrepancies exist between MR studies, we suggest the underlying reasons. A number of studies conclude that there is a causal link between blood lipids and risk of ALS; replication across different datasets and even different populations adds confidence. For other putative risk factors, such as smoking and immune function, MR studies have provided cause for doubt. We highlight the use of positive control analyses in choosing exposure SNPs to make up the MR instrument, use of SNP clumping to avoid false positive results due to SNPs in linkage, and the importance of multiple testing correction. We discuss the implications of survival bias for study of late age of onset diseases such as ALS, and make recommendations to mitigate this potentially important confounder. For MR to be useful to the ALS field, high methodological standards must be applied to ensure reproducibility. MR is already an impactful tool but poor quality studies will lead to incorrect interpretations by a field which includes non-statisticians, wasted resources and missed opportunities.
Background Much progress has been made in mapping genetic abnormalities linked to amyotrophic lateral sclerosis (ALS), but the majority of cases still present with no known underlying cause. Furthermore, even in families with a shared genetic abnormality there is significant phenotypic variability, suggesting that non-genetic elements may modify pathogenesis. Identification of such disease-modifiers is important as they might represent new therapeutic targets. A growing body of research has begun to shed light on the role played by the gut microbiome in health and disease with a number of studies linking abnormalities to ALS. Main body The microbiome refers to the genes belonging to the myriad different microorganisms that live within and upon us, collectively known as the microbiota. Most of these microbes are found in the intestines, where they play important roles in digestion and the generation of key metabolites including neurotransmitters. The gut microbiota is an important aspect of the environment in which our bodies operate and inter-individual differences may be key to explaining the different disease outcomes seen in ALS. Work has begun to investigate animal models of the disease, and the gut microbiomes of people living with ALS, revealing changes in the microbial communities of these groups. The current body of knowledge will be summarised in this review. Advances in microbiome sequencing methods will be highlighted, as their improved resolution now enables researchers to further explore differences at a functional level. Proposed mechanisms connecting the gut microbiome to neurodegeneration will also be considered, including direct effects via metabolites released into the host circulation and indirect effects on bioavailability of nutrients and even medications. Conclusion Profiling of the gut microbiome has the potential to add an environmental component to rapidly advancing studies of ALS genetics and move research a step further towards personalised medicine for this disease. Moreover, should compelling evidence of upstream neurotoxicity or neuroprotection initiated by gut microbiota emerge, modification of the microbiome will represent a potential new avenue for disease modifying therapies. For an intractable condition with few current therapeutic options, further research into the ALS microbiome is of crucial importance.
Damage to the sensory hair cells and the spiral ganglion neurons of the cochlea leads to deafness. Induced pluripotent stem cells (iPSCs) are a promising tool to regenerate the cells in the inner ear that have been affected by pathology or have been lost. To facilitate the clinical application of iPSCs, the reprogramming process should minimize the risk of introducing undesired genetic alterations while conferring the cells the capacity to differentiate into the desired cell type. Currently, reprogramming induced by synthetic mRNAs is considered to be one of the safest ways of inducing pluripotency, as the transgenes are transiently delivered into the cells without integrating into the genome. In this study, we explore the ability of integration-free human-induced pluripotent cell lines that were reprogrammed by mRNAs, to differentiate into otic progenitors and, subsequently, into hair cell and neuronal lineages. hiPSC lines were induced to differentiate by culturing them in the presence of fibroblast growth factors 3 and 10 (FGF3 and FGF10). Progenitors were identified by quantitative microscopy, based on the coexpression of otic markers PAX8, PAX2, FOXG1, and SOX2. Otic epithelial progenitors (OEPs) and otic neuroprogenitors (ONPs) were purified and allowed to differentiate further into hair cell-like cells and neurons. Lineages were characterised by immunocytochemistry and electrophysiology. Neuronal cells showed inward Na+ (INa) currents and outward (Ik) and inward K+ (IK1) currents while hair cell-like cells had inward IK1 and outward delayed rectifier K+ currents, characteristic of developing hair cells. We conclude that human-induced pluripotent cell lines that have been reprogrammed using nonintegrating mRNAs are capable to differentiate into otic cell types.
This study demonstrates that hMSCs can be driven to express key genes found in the otic lineages and thereby promotes their status as candidates for regenerative therapies for deafness.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease which affects 1/350 individuals in the United Kingdom. The cause of ALS is unknown in the majority of cases. Two sample Mendelian randomisation (MR) enables causal inference between an exposure, such as the serum concentration of a specific metabolite, and disease risk. We obtained genome-wide association study (GWAS) summary statistics for serum concentrations of 566 metabolites which were population matched with a GWAS study of ALS. For each metabolite we performed MR using an inverse variance weighted estimate for significance testing. After stringent Bonferroni multiple testing correction our unbiased screen revealed three metabolites which were significantly linked to risk of ALS: Estrone-3-sulfate and bradykinin were protective, which is consistent with literature describing a male preponderance of ALS and a preventive effect of angiotensin-converting enzyme inhibitors which inhibit breakdown of bradykinin. Serum isoleucine was positively associated with ALS risk. All three metabolites were supported by robust MR measures and sensitivity analyses; estrone-3-sulfate and isoleucine were confirmed in a validation ALS GWAS. Estrone-3-sulfate is metabolised to the more active estradiol by the enzyme 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1); further MR demonstrated a protective effect of estradiol and rare variant analysis showed that missense variants within HSD17B1, the gene encoding 17β-HSD1, modify risk for ALS. Finally, in a zebrafish model of C9ORF72-ALS we present evidence that estradiol is neuroprotective. Isoleucine is metabolised via methylmalonyl-CoA mutase encoded by the gene MMUT in a reaction which consumes vitamin B12. Multivariable MR revealed that the toxic effect of isoleucine is dependent on depletion of vitamin B12; consistent with this, rare variants which reduce function of MMUT are protective against ALS. We propose that ALS patients and family members with high serum isoleucine levels should be offered supplementation with vitamin B12.
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