Cerebral Vitamin B5 (D-Pantothenic Acid) Deficiency as a Potential Cause of Metabolic Perturbation and Neurodegeneration in Huntington’s Disease

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the HTT gene. HD usually manifests in mid-life with loss of GABAergic projection neurons from the striatum accompanied by progressive atrophy of the putamen followed by other brain regions, but linkages between the genetics and neurodegeneration are not understood. We measured metabolic perturbations in HD-human brain in a case-control study, identifying pervasive lowering of vitamin B5, the obligatory precursor of coenzyme A (CoA) that is essential for normal intermediary metabolism. Cerebral pantothenate deficiency is a newly-identified metabolic defect in human HD that could potentially: (i) impair neuronal CoA biosynthesis; (ii) stimulate polyol-pathway activity; (iii) impair glycolysis and tricarboxylic acid cycle activity; and (iv) modify brain-urea metabolism. Pantothenate deficiency could lead to neurodegeneration/dementia in HD that might be preventable by treatment with vitamin B5.

Gut Microbiota and Metabolome Alterations Associated with Parkinson’s Disease

“…Several genera of intestinal Firmicutes bacteria express crucial factors for vitamin B3 synthesis (42,43), suggesting that these bacteria might affect the metabolism and bioavailability of these vitamins in the gut. Vitamin B5 is the primary precursor of coenzyme A, and its deficiency might be involved in the alteration of the citric acid cycle, causing defective energy levels, a finding shared by several neurodegenerative disorders, such as PD, Huntington's disease, and Alzheimer's disease (44).…”

B Vitamins and Fatty Acids: What Do They Share with Small Vessel Disease-Related Dementia?

“…It is essential for fatty acid synthesis and β-oxidation, and for cholesterol, lipid, and sphingolipid biosynthesis, as well as for the production of steroid hormones and neurotransmitters, i.e., acetylcholine [195,201,250,251]. Further, acetyl-CoA plays a role in global histone acetylation, modulating gene expression, cell growth, and proliferation [252,253]. Pantothenic acid, due to the increase of CoA, exerts an antioxidative property [254,255,256] and influences inflammatory factors, such as C-reactive protein (CRP) [257].…”

Protection from the Pathogenesis of Neurodegenerative Disorders, including Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Huntington’s Disease, and Parkinson’s Diseases, through the Mitigation of Reactive Oxygen Species

“…Huntington's disease is a genetic neurodegenerative disorder characterized by the selective degeneration of neurons. This degeneration results in progressive disabilities, including motor dysfunction and both cognitive and psychiatric de iciencies [104][105][106]. HD is associated with polyglutamine-expansion; thus, the disease primarily impacts the cerebral cortex and striatum [107,108].…”

“…Huntington's disease is caused by a repeat expansion of cytosine-adenine-guanine (CAG) in the huntingtin gene [105,113,114]. The mutant huntingtin protein (mHTT) leads to neuronal dysfunction before ultimately causing cell death due to excitotoxicity, transcriptional de iciencies, in lammation, oxidative damage, mitochondrial dysfunction, and apoptosis [112,115,116].…”

“…According to various studies (Table 1), vitamin B 5 de iciency may cause dementia and neurodegeneration in HD patients, and treatments that include B 5 may help prevent the progression of HD [105]. Plant-derived polyphenols are ubiquitous compounds characterized by numerous pharmacological properties, including antioxidant, anti-in lammatory, mitochondrial protective, and anti-apoptotic activities [95,42].…”