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Results of a recent study published in Nature Communications provide encouraging results in the study of Huntington’s disease, suggesting a new physiological target in this progressive and currently incurable neurodegenerative disease. Using single-nucleus RNA sequencing (snRNAseq), a method of studying the transcriptome (gene expression) in the nucleus only (versus the entire cell), researchers attempted to map out the specific pathologies found in both animal and post-mortem human tissues. Deficits were found in the maturation of oligodendrocytes (Ols) and their precursors, and these deficits were related to abnormalities in lipid and glucose metabolism. Furthermore, the genes PRKCE (Protein kinase C epsilon) and Tpk1 (Thiamine Pyrophosphokinase 1) appeared to play a central role in the associated pathology, and supplementation with thiamine and biotin in the animal model restored normal OL maturation.
Huntington’s disease is a type of repeat expansion disease characterized by an autosomal dominant CAG repeat, i.e., a repeat of the trinucleotide sequence in the gene encoding the huntingtin (HTT) protein. The number of repeats varies between people, with an intermediate risk of developing Huntington’s disease among carriers with between 26-35 repeats of this sequence, with 36 or more repeats marked by much more significant risk. Each CAG codes for the amino acid glutamine, and thus the huntingtin protein has a variable number of glutamine residues depending on the number of repeats. The number of repeats has been positively correlated with the age of onset and penetrance of the disease, with the mutant huntingtin protein (mHTT) considered causal.
Many studies have pointed to the diverse detrimental effects of mHTT, including neuronal loss throughout various regions of the brain, neuroinflammation, oxidative damage, mitochondrial deficits, and more. For example, decreased activity in all four complexes of the Kreb’s cycle have been documented, as well as a reduction in the mitochondrial membrane potential and an upregulation of glycolysis. mHTT appears to inhibit the import of proteins into the mitochondria by binding to a specific complex found in the intermembrane space of the mitochondria. mHTT also blocks expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), a key regulator of multiple functions, including mitochondrial biogenesis.
While many preclinical studies suggested a possible benefit of nutrients associated with improving mitochondrial function or reducing oxidative stress, clinical trials so far have generally been disappointing. For example, the compound cysteamine was shown to be neuroprotective in animal trials, yet in the sole human clinical trial no significant difference was observed after 18 months, though a post-hoc analysis did suggest a potential reduction in deterioration for those patients with the most severe disease. Similarly, CoQ10 at a dose of 2400mg per day was not found to have a significant effect compared to placebo over a 5-year clinical trial, despite considerable preclinical trial data demonstrating its value. Creatine monohydrate at up to 40g per day also lacked clinical benefit in a randomized trial, as did 1g twice per day ethyl-EPA.
Multiple clinical trials are in progress for other nutrients, including resveratrol and melatonin, and it is plausible that other more bioavailable forms of nutrients such as curcumin, quercetin, alpha-lipoic acid, etc. may have benefit, particularly when provided earlier in life and potentially in combination with other compounds than when used in isolation. It’s also worth noting that a recent systematic review suggests training in cognitive exercises, alone and when combined with exercise, may have cognitive and psychosocial benefits.
Abnormalities in glucose and lipid metabolism in people with Huntington’s disease, as observed in the above Nature Communications study and elsewhere, seem to be implicated in several neurodegenerative disorders. For example, in a 2019 study published in Brain, using gene therapy in an animal model to restore the gene CYP46A1 (responsible for the degradation of cholesterol), was shown to compensate for many mHTT-induced dysfunctions. The Nature Communications study is particularly hopeful, as multiple mHTT-related abnormalities seemed to be associated with dysregulated metabolic genes (including those related to glycolysis, fatty acid, and pyruvate metabolism pathways), including Tpk1, Ogt, Galnt13 and Dgkx genes, some of which were corrected by nutritional intervention in the animal model.
For example, Tpk1 was shown to be the most highly dysregulated gene in this study; its protein product, the enzyme Thiamine Pyrophosphokinase 1, converts thiamine to thiamine-pyrophosphate (TPP). TPP in turn is required for the conversion of pyruvate to acetyl-CoA, which itself is intimately tied to many metabolic functions, including the maturation of oligodendrocytes. Acetyl-CoA is also required for the formation of diacylglycerol, a metabolite found to be reduced in the brains of people with Huntington’s disease, and necessary for the activation of PRKCE. Thus, supplying high dose thiamine and biotin (biotin has been utilized in other basal ganglia diseases) may override these metabolic bottlenecks; in the animal model used in this study, supplementation “rescued” many of the dysregulated genes in all cell types (including neurons), as well those related to oligodendrocyte maturation. A clinical trial evaluating the use of thiamine and biotin supplementation among people with Huntington’s is now in process in Spain.
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