Regulation of one-carbon metabolism may open new avenues to slow down the initiation and progression of Huntington’s disease

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 18(11), P. 2401 - 2402

Published: March 11, 2023

Huntington’s disease (HD) (OMIM 143100) is an autosomal dominant neurodegenerative disorder caused by a monogenic mutation in the huntingtin gene (HTT), which induces typical midlife onset and age-dependent progression with major symptoms including choreic movements, psychiatric disorders, cognitive impairment (Gusella et al., 2021). After 1993 discovery of pathogenic expansion CAG trinucleotide repeat beyond 35 HTT exon 1 as causative factor for HD, many animal, mammalian cell yeast models expressing mutant (mHtt) abnormal repeats have been created to study repeat-induced toxicity (Naphade 2019; Gusella With these studies on human subjects, some important insights into initiation mechanisms elucidated, but underlying mHtt-induced are still not yet fully understood no disease-modifying treatment sight (Caron 2018; Veldman Yang, Previous revealed that mHtt length-dependent, longer associated earlier more aggressive At molecular level, codes polyglutamine (polyQ) tract. In normal population, proteins contain 6Q 35Q acting scaffold various interactions essential brain development before birth, while (≥ 36Q repeats) cause protein aggregation numerous pathophysiological changes (Veldman Naphade 2019). The formation insoluble aggregates pathological hallmark HD even though clear results indicate whether or result pathogenesis Neuropathological analysis post-mortem brains from patients animals dramatic degeneration neurons initiated striatum deeper layers cerebral cortex, followed other regions (Rangel-Barajas Rebec, 2016; 2018). complex involving dysregulation cellular processes, such transcription, proteostasis, mitochondrial function, chromatin modification, resulting progressive neuronal loss Although inherited carriers could be identified symptom onset, treatments targeting suppression mRNA transcript unavailable A scarcity aimed at understanding early affected pathways may reason lack effective (Hung 2022). Therefore, it explore novel model systems investigate pathways, might facilitate our aid us develop prevention strategies. Recent suggest folate-mediated one-carbon (C1) metabolism play role diseases (NDDs), (Ducker Rabinowitz, 2017; Zsindely 2021; Lionaki C1 comprises folate cycle, methionine transsulfuration pathway (Figure 1) plays roles physiological processes across organisms Gorelova cycles enable cells generate units. latter used synthesis purine thymidine, methylation DNA, RNA, histone proteins, known effects regulating expression levels transcriptionally and/or translationally maintaining genome stability. involves transfer sulfur homocysteine cysteine, leading generation several metabolites, antioxidant glutathione gaseous signaling molecule hydrogen sulfide. Stringent control this via regulation key enzymes cystathionine β-synthase γ-lyase (CSE) maintenance optimal function. Depletion CSE, enzyme catalyzing cysteine has observed its thought responsible neurotoxicity oxidative stress (Paul 2014).Figure 1: relationship between BH4 metabolism.Expression exon-1 (mHttex1) affects both murine plant metabolism. See text details. Red arrows stand mammal-specific metabolism, green plant-specific gray both. Solid lines represent dashed postulated Hung al. (2022).The generic term “folate” includes tetrahydrofolate (THF) derivatives, group tripartite molecules carrying units varying oxidation states. Plants autotrophs can synthesize de novo, mammals depend dietary folates. Diet-derived folic acid (vitamin B9) first reduced dihydrofolate then converted metabolically active form THF two successive NADPH-dependent reductions catalyzed same reductase (DHFR) enters cycle. Because involvement multiple tightly regulated intracellular metabolites cofactors. Any disturbance either cycle lead altered transcriptional translational activities genome-wide, ultimately affecting survival proliferation 2017). research directly implicating scarce, shown modulates DNA methylation, acetylation thereby activity Ratovitski 2022), inducing instability through meiotic transmission These imply likely HD. Moreover, deficiency reported increase risk Alzheimer’s Parkinson’s disease, neural tube defects S-adenosylmethionine (SAM), vitamin B6, B9, B12 supplements exert beneficial NDDs reduce dementia supplementation increasing production Golgi stressor provide protection benefits 2014; Sbodio Polymorphisms metabolism-related genes also found All strong link along NDDs; however, connection them remains elusive. Recently, we developed plant-based system stably mHttex1 (HTT tobacco plants investigation mHtt-mediated confirmation was integrated well properly transcribed translated, toxic expanded polyQ growth, especially root hair development, were length-dependent similar those animal models. We believe all transgenic resulted gain-of-function since ortholog. This helps avoid any endogenous HTT. quantitative proteomic Httex1Q63 (abnormal) Httex1Q21 (normal line) young roots polyQ63 triggered widespread remodeling Most importantly, autotrophic feature ability folates novo allowed discover hitherto unreported biosynthesis findings supported showing reducing abundance GTP cyclohydrolase I (GTPCH) 6-fold significantly 38 out 42 SAM-dependent methyltransferases (SAM-MTases) metabolism-associated 1.5-fold reduction, FDR-corrected P < 0.05). plants, GTPCH rate-limiting catalyzes step biosynthesis, SAM-MTases critical methyl groups biomolecules (Gorelova decrease impairs Since there large evolutionary distance animals, further validated (4-week-old) R6/2 mice mammals, reaction convert guanosine triphosphate (GTP) dihydroneopterin (DHPTP) 1). However, produced DHPTP (DHF) enter transformed tetrahydrobiopterin (BH4) series reactions. regulates BH4, cofactor aromatic amino hydroxylases produce monoamine neurotransmitters, DHFR utilization alternate reduction dihydrobiopterin (BH2) back discovered impaired total tissues isolated 4-week-old mice. glycine increased 26.5% tissues, serine 17.9% plasma. acids sources Thus, showed only C1-related juvenile stage. Our mouse event “missing links” connecting help explain previously common pathogenesis, dysfunction regulation, maintenance, transgenerational epigenetic inheritance, imprinting (Zsindely 2021), inheritance linked alterations Additionally, locus arginines differentially methylated methylation. Concerning established C5 position cytosine residue SAM 5-methylcytosine methyltransferases. Available evidences show levels, accumulation potent methyltransferase inhibitor S-adenosylhomocysteine suppresses arginine transferred terminal nitrogen atom residues (Ratovitski Arginine functions regulator transcription. would affect turn disturb production, subsequently impair addition, dual conversion BH2 interconnects (Xu 2014). Genetic insufficient 2014), GTPCH-deficient exhibited dopamine, phenylalanine, infancy-onset motor impairments (Jiang mice, GTPCH- DHFR-associated neurotransmitter disturbed very stage Interestingly, unlike uniformly suppressed cortex induced when compared age wild-type inverse regions. It much severe than aberrant communication considered striatal Under healthy conditions, cortico-striatal dopamine being perturbation imbalance thus contribute selective vulnerability 2016). Further are, warranted understand starts, how ratio during progression, what relationships among DHFR, GTPCH, folate, biosynthesis. addition least eight expansion-mediated share features neurodegeneration genetic causes diseases, polyQ-induced damage time appear already too advanced successful. strategy preventing impeding will promising improving health quality life carriers. nature simple PCR test diagnosis reliable identification symptomatic onset. Theoretically, premanifest phase prevent reverse once identified. Given importance central nervous Ducker Jiang 2019), certain C1/BH4 significant contributing factors progression. open new avenues perhaps diseases. work National Institute General Medical Sciences grant (SC1GM111178) JX. C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y

Language: Английский

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Deregulated Transcriptome as a Platform for Adrenal Huntington’s Disease-Related Pathology

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(4), P. 2176 - 2176

Published: Feb. 11, 2024

Huntington's disease (HD) is a neurodegenerative disorder that affects mainly the central nervous system (CNS) by inducing progressive deterioration in both its structure and function. In recent years, there has been growing interest impact of HD on peripheral tissue Herein, we used R6/2 mouse model to investigate influence adrenal gland functioning. A transcriptomic analysis conducted using well-established quantitative method, an Affymetrix array, revealed changes gene expression compared genetic background controls. For first time, identified disruptions cholesterol sterol metabolism, blood coagulation, xenobiotic metabolism glands. This study showed disrupted these genes may contribute underlying mechanisms disease. Our findings developing better understanding progression aid development novel diagnostic or therapeutic approaches.

Language: Английский

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Gene editing for HD: Therapeutic prospects

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 551 - 570

Published: Jan. 1, 2024

Language: Английский

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A longitudinal study of the progression of Huntington’s disease and oropharyngeal dysphagia: A four-case follow-up

Revista CEFAC, Journal Year: 2024, Volume and Issue: 26(2)

Published: Jan. 1, 2024

Huntington's disease (HD) is a neurodegenerative disorder, with dysphagia being common symptom of the disease. Few studies established relationship between neuromotor impairment and dysphagia. There also lack described therapeutic approaches for in HD. This study aimed to better understand progression neurological clinical aspects, instrumental swallowing management four patients presented HD an outpatient follow-up setting. The longitudinal period was 36 43 months through neuroclinical assessments (Unified Disease Rating Scale) fiberoptic endoscopic evaluations. Case 1 - moderate decline independence safe swallowing. 2 motor impairment, during follow-up. 3 longer duration increased associated moderate/severe 4 duration, need assistance perform daily activities, severe palliative care, considering family decision exclusive oral feeding. revealed that damage not directly related development. case series demonstrates importance settings evaluations careful consideration early care patients.

Language: Английский

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The impact of diagnosing provider type on longitudinal care for patients with newly diagnosed Huntington’s Disease

Journal of Medical Economics, Journal Year: 2024, Volume and Issue: 27(1), P. 1348 - 1357

Published: Oct. 7, 2024

Aims This study evaluated the association between provider types for patients with newly diagnosed Huntington's disease (HD) and healthcare resource utilization (HCRU), costs, treatment patterns.

Language: Английский

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