Metabolites involved in the biosynthesis of aminoacyl-tRNA synthesis could play an important role in the pathogenesis of Huntington’s disease (HD), according to a study recently published in Genes.

“This study improves our understanding of molecular biomarker connections and, importantly, increases our knowledge of metabolic alterations driving HD progression,” the authors wrote.

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This experimental research utilized postmortem brain tissue samples from HD-affected individuals and healthy controls, aiming to understand the interplay between DNA methylation and the metabolome to gain deeper insights into the disease’s development.

Investigators analyzed samples from 14 postmortem HD cases and 14 controls. Control subjects displayed no signs of HD’s pathology or recent use of dementia-associated medications. The study focused on 2 brain regions, the striatum and frontal lobe, for metabolic profiling, while epigenetic analysis concentrated solely on the frontal lobe.

Interestingly, even subtle changes in diet and nutrition could induce epigenetic changes that might, in turn, promote the development of certain diseases. The data analysis unveiled a significant correlation between phenylalanine and methionine and specific CpGs (genomic sites with clusters of unmethylated cytosines followed by guanine). Although neither phenylalanine nor methionine directly causes HD, they can impact neurotransmitter levels, which are crucial in HD’s pathogenesis. Furthermore, the study identified several genes significantly correlated with these metabolites, such as GPC6, CSNK1G3, and PCNX, known for their roles in synaptic function and neurogenesis.

Notably, the study revealed perturbations in the aminoacyl-tRNA biosynthesis pathway, a crucial mechanism in protein synthesis and translation precision. This pathway’s dysregulation has previously been associated with HD.

Several genes, including SEPSECS, were highlighted in this context. SEPSECS is responsible for producing selenocysteine, an antioxidant amino acid with potential neuroprotective properties. This finding suggests that selenocysteine and other antioxidants might play a role in mitigating oxidative stress, a hallmark of HD’s pathogenesis.

“Understanding the complex interplay between metabolites and genes in HD has the potential to uncover novel therapeutic targets for this devastating disease,” the authors wrote.


Vishweswaraiah S, Yilmaz A, Saiyed N, et al. Integrative analysis unveils the correlation of aminoacyl-tRNA biosynthesis metabolites with the methylation of the SEPSECS gene in Huntington’s disease brain tissue. Genes. Published online September 2, 2023. doi:10.3390/genes14091752