ABSTRACT
Spinocerebellar ataxia is a phenotypically and genetically heterogeneous group of autosomal dominant-inherited degenerative disorders. The gene mutation spectrum includes dynamic expansions, point mutations, duplications, insertions, and deletions of varying lengths. Dynamic expansion is the most common form of mutation. Mutations often result in indistinguishable clinical phenotypes, thus requiring validation using multiple genetic testing techniques. Depending on the type of mutation, the pathogenesis may involve proteotoxicity, RNA toxicity, or protein loss-of-function. All of which may disrupt a range of cellular processes, such as impaired protein quality control pathways, ion channel dysfunction, mitochondrial dysfunction, transcriptional dysregulation, DNA damage, loss of nuclear integrity, and ultimately, impairment of neuronal function and integrity which causes diseases. Many disease-modifying therapies, such as gene editing technology, RNA interference, antisense oligonucleotides, stem cell technology, and pharmacological therapies are currently under clinical trials. However, the development of curative approaches for genetic diseases remains a global challenge, beset by technical, ethical, and other challenges. Therefore, the study of the pathogenesis of spinocerebellar ataxia is of great importance for the sustained development of disease-modifying molecular therapies.
ABSTRACT
Background: It has been suggested in several observational studies that migraines are associated with the gut microbiota. It remains unclear, however, how the gut microbiota and migraines are causally related. Methods: We performed a bidirectional two-sample mendelian randomization study. Genome-wide association study (GWAS) summary statistics for the gut microbiota were obtained from the MiBioGen consortium (n = 18,340) and the Dutch Microbiota Project (n = 7,738). Pooled GWAS data for plasma metabolites were obtained from four different human metabolomics studies. GWAS summary data for migraine (cases = 48,975; controls = 450,381) were sourced from the International Headache Genetics Consortium. We used inverse-variance weighting as the primary analysis. Multiple sensitivity analyses were performed to ensure the robustness of the estimated results. We also conducted reverse mendelian randomization when a causal relationship between exposure and migraine was found. Results: LachnospiraceaeUCG001 (OR = 1.12, 95% CI: 1.05-1.20) was a risk factor for migraine. Blautia (OR = 0.93, 95% CI: 0.88-0.99), Eubacterium (nodatum group; OR = 0.94, 95% CI: 0.90-0.98), and Bacteroides fragilis (OR = 0.97, 95% CI: 0.94-1.00) may have a suggestive association with a lower migraine risk. Functional pathways of methionine synthesis (OR = 0.89, 95% CI: 0.83-0.95) associated with microbiota abundance and plasma hydrocinnamate (OR = 0.85, 95% CI: 0.73-1.00), which are downstream metabolites of Blautia and Bacteroides fragilis, respectively, may also be associated with lower migraine risk. No causal association between migraine and the gut microbiota or metabolites was found in reverse mendelian randomization analysis. Both significant horizontal pleiotropy and significant heterogeneity were not clearly identified. Conclusion: This Mendelian randomization analysis showed that LachnospiraceaeUCG001 was associated with an increased risk of migraine, while some bacteria in the gut microbiota may reduce migraine risk. These findings provide a reference for a deeper comprehension of the role of the gut-brain axis in migraine as well as possible targets for treatment interventions.
