Huntingtin
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Současné studie naznačují možnou důležitou úlohu melatoninu v Huntingtonově nemoci (HN) a jeho možné terapeutické využití při léčbě této nemoci. HN je dědičné neurodegenerativní onemocnění, které doprovází snižování hladiny melatoninu s postupem onemocnění. U normálních (nenádorových) buněk působí melatonin antiapoptoticky díky svým antioxidačním vlastnostem a schopnosti zabránit aktivaci proteinu p53. Dále melatonin zvyšuje expresi BDNF (brain derived neurotrophic factor) a dalších neuroprotektivních faktorů. Cílem této studie bylo stanovit netoxickou dávku melatoninu pro primární kožní fibroblasty izolované z transgenních miniprasat pro N‑koncovou část lidského mutovaného huntingtinu (TgHD) a popsat efekt tohoto ošetření na tyto buňky vystavené genotoxickému stresu. Buňky byly kultivovány v médiu obohaceném různými dávkami melatoninu. Analýzou proliferačních křivek získaných mikroskopováním živých buněk v pravidelných časových intervalech jsme stanovili efekt různých koncentrací melatoninu.Ukázali jsme, že vyšší dávky melatoninu jsou pro primární prasečí buňky toxické. Je zajímavé, že TgHD buňky byly oproti kontrolním buňkám více citlivé k tímto dávkám melatoninu. Stanovili jsme efektivní dávku melatoninu a současně jsme ukázali její efekt na proliferaci u buněk vystavených genotoxickému stresu. Klíčová slova: Huntingtonova choroba – melatonin – mikroskopie buněk v čase – miniprasečí model –proliferační křivky – kožní fibroblasty Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy. Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů.
According to the recent studies, melatonin might play an important role in Huntington's disease (HD) and act as a novel therapeutic approach in the treatment of the disease. HD, the inherited neurodegenerative disorder, is accompanied by gradual melatonin reduction as it progresses. Melatonin in normal cells (non‑tumor) has the anti‑apoptotic ability due to its antioxidant property and its ability to prevent the activation of p53. Furthermore, melatonin increases the expression of BDNF (brain derived neurotrophic factor) and other neuroprotective factors. The aim of this study was to evaluate the nontoxic dose of melatonin for primary skin fibroblasts isolated from minipigs transgenic for the N‑terminal part of human mutated huntingtin (TgHD), and the effect of melatonin treatment to these cells exposed to genotoxic stress. Cells were cultured in medium supplemented with different doses of melatonin. Using time lapse microscopy, we estimated the effect of decreasing melatonin concentrations by analyzing the proliferation curves. We show that higher doses of melatonin are toxic for primary porcine fibroblasts. Interestingly, TgHD cells were more sensitive to these doses of melatonin treatment than wild type cells. We evaluated the effective dose of melatonin and demonstrated its rescue proliferative effect on porcine primary cells exposed to genotoxic stress.
- Klíčová slova
- mikroskopie buněk v čase, kožní fibroblasty, proliferační křivky, huntingtin,
- MeSH
- časové faktory MeSH
- fibroblasty * účinky léků MeSH
- geneticky modifikovaná zvířata MeSH
- Huntingtonova nemoc * MeSH
- kůže MeSH
- melatonin * aplikace a dávkování farmakologie terapeutické užití MeSH
- mikroskopie MeSH
- miniaturní prasata MeSH
- modely u zvířat MeSH
- mutace MeSH
- poškození DNA MeSH
- prasata MeSH
- proliferace buněk MeSH
- proteiny nervové tkáně genetika MeSH
- statistika jako téma MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- srovnávací studie MeSH
BACKGROUND: Huntington's disease is induced by CAG expansion in a single gene coding the huntingtin protein. The mutated huntingtin (mtHtt) primarily causes degeneration of neurons in the brain, but it also affects peripheral tissues, including testes. OBJECTIVE: We studied sperm and testes of transgenic boars expressing the N-terminal region of human mtHtt. METHODS: In this study, measures of reproductive parameters and electron microscopy (EM) images of spermatozoa and testes of transgenic (TgHD) and wild-type (WT) boars of F1 (24-48 months old) and F2 (12-36 months old) generations were compared. In addition, immunofluorescence, immunohistochemistry, Western blot, hormonal analysis and whole-genome sequencing were done in order to elucidate the effects of mtHtt. RESULTS: Evidence for fertility failure of both TgHD generations was observed at the age of 13 months. Reproductive parameters declined and progressively worsened with age. EM revealed numerous pathological features in sperm tails and in testicular epithelium from 24- and 36-month-old TgHD boars. Moreover, immunohistochemistry confirmed significantly lower proliferation activity of spermatogonia in transgenic testes. mtHtt was highly expressed in spermatozoa and testes of TgHD boars and localized in all cells of seminiferous tubules. Levels of fertility-related hormones did not differ in TgHD and WT siblings. Genome analysis confirmed that insertion of the lentiviral construct did not interrupt any coding sequence in the pig genome. CONCLUSIONS: The sperm and testicular degeneration of TgHD boars is caused by gain-of-function of the highly expressed mtHtt.
- MeSH
- genetické vektory MeSH
- geneticky modifikovaná zvířata MeSH
- Huntingtonova nemoc metabolismus patologie MeSH
- Lentivirus genetika MeSH
- lidé MeSH
- miniaturní prasata MeSH
- modely nemocí na zvířatech MeSH
- mutace * MeSH
- počet spermií MeSH
- prasata MeSH
- proliferace buněk fyziologie MeSH
- protein huntingtin genetika metabolismus MeSH
- spermie metabolismus patologie MeSH
- stárnutí metabolismus patologie MeSH
- testis metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The pathogenic effect of mutant HTT (mHTT) which causes Huntington disease (HD) are not restricted to nervous system. Such phenotypes include aberrant immune responses observed in the HD models. However, it is still unclear how this immune dysregulation influences the innate immune response against pathogenic infection. In the present study, we used transgenic Drosophila melanogaster expressing mutant HTT protein (mHTT) with hemocyte-specific drivers and examined the immune responses and hemocyte function. We found that mHTT expression in the hemocytes did not affect fly viability, but the numbers of circulating hemocytes were significantly decreased. Consequently, we observed that the expression of mHTT in the hemocytes compromised the immune responses including clot formation and encapsulation which lead to the increased susceptibility to entomopathogenic nematode and parasitoid wasp infections. In addition, mHTT expression in Drosophila macrophage-like S2 cells in vitro reduced ATP levels, phagocytic activity and the induction of antimicrobial peptides. Further effects observed in mHTT-expressing cells included the altered production of cytokines and activation of JAK/STAT signaling. The present study shows that the expression of mHTT in Drosophila hemocytes causes deficient cellular and humoral immune responses against invading pathogens. Our findings provide the insight into the pathogenic effects of mHTT in the immune cells.
- MeSH
- buněčné linie MeSH
- Drosophila melanogaster MeSH
- exprese genu * MeSH
- geneticky modifikovaná zvířata MeSH
- hemocyty imunologie MeSH
- humorální imunita * MeSH
- lidé MeSH
- protein huntingtin genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Huntington's disease (HD) is a devastating neurodegenerative disorder caused by CAG triplet expansions in the huntingtin gene. Oxidative stress is linked to HD pathology, although it is not clear whether this is an effect or a mediator of disease. The transgenic (TgHD) minipig expresses the N-terminal part of human-mutated huntingtin and represents a unique model to investigate therapeutic strategies towards HD. A more detailed characterization of this model is needed to fully utilize its potential. METHODS: In this study, we focused on the molecular and cellular features of fibroblasts isolated from TgHD minipigs and the wild-type (WT) siblings at different ages, pre-symptomatic at the age of 24-36 months and with the onset of behavioural symptoms at the age of 48 months. We measured oxidative stress, the expression of oxidative stress-related genes, proliferation capacity along with the expression of cyclin B1 and D1 proteins, cellular permeability, and the integrity of the nuclear DNA (nDNA) and mitochondrial DNA in these cells. RESULTS: TgHD fibroblasts isolated from 48-month-old animals showed increased oxidative stress, which correlated with the overexpression of SOD2 encoding mitochondrial superoxide dismutase 2, and the NEIL3 gene encoding DNA glycosylase involved in replication-associated repair of oxidized DNA. TgHD cells displayed an abnormal proliferation capacity and permeability. We further demonstrated increased nDNA damage in pre-symptomatic TgHD fibroblasts (isolated from animals aged 24-36 months). CONCLUSIONS: Our results unravel phenotypic alterations in primary fibroblasts isolated from the TgHD minipig model at the age of 48 months. Importantly, nDNA damage appears to precede these phenotypic alterations. Our results highlight the impact of fibroblasts from TgHD minipigs in studying the molecular mechanisms of HD pathophysiology that gradually occur with age.
- MeSH
- buněčné dělení MeSH
- fenotyp MeSH
- fibroblasty metabolismus MeSH
- geneticky modifikovaná zvířata MeSH
- lidé MeSH
- miniaturní prasata MeSH
- mitochondriální DNA genetika MeSH
- N-glykosylhydrolasy biosyntéza genetika MeSH
- oxidační stres MeSH
- peroxidace lipidů MeSH
- poškození DNA MeSH
- prasata MeSH
- primární buněčná kultura MeSH
- protein huntingtin genetika metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- regulace genové exprese MeSH
- stárnutí metabolismus MeSH
- superoxiddismutasa biosyntéza genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Previously, we showed strong huntingtin reduction and prevention of neuronal dysfunction in HD rodents using an engineered microRNA targeting human huntingtin, delivered via adeno-associated virus (AAV) serotype 5 vector with a transgene encoding an engineered miRNA against HTT mRNA (AAV5-miHTT). One of the challenges of rodents as a model of neurodegenerative diseases is their relatively small brain, making successful translation to the HD patient difficult. This is particularly relevant for gene therapy approaches, where distribution achieved upon local administration into the parenchyma is likely dependent on brain size and structure. Here, we aimed to demonstrate the translation of huntingtin-lowering gene therapy to a large-animal brain. We investigated the feasibility, efficacy, and tolerability of one-time intracranial administration of AAV5-miHTT in the transgenic HD (tgHD) minipig model. We detected widespread dose-dependent distribution of AAV5-miHTT throughout the tgHD minipig brain that correlated with the engineered microRNA expression. Both human mutant huntingtin mRNA and protein were significantly reduced in all brain regions transduced by AAV5-miHTT. The combination of widespread vector distribution and extensive huntingtin lowering observed with AAV5-miHTT supports the translation of a huntingtin-lowering gene therapy for HD from preclinical studies into the clinic.
- MeSH
- Dependovirus genetika MeSH
- expanze trinukleotidových repetic genetika MeSH
- genetická terapie metody MeSH
- genetické vektory genetika MeSH
- geneticky modifikovaná zvířata MeSH
- Huntingtonova nemoc genetika metabolismus terapie MeSH
- lidé MeSH
- mikro RNA genetika metabolismus MeSH
- miniaturní prasata MeSH
- modely nemocí na zvířatech MeSH
- prasata MeSH
- protein huntingtin genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Huntington's disease (HD) is a fatal neurodegenerative disease caused by a genetic expansion of the CAG repeat region in the huntingtin (HTT) gene. Studies in HD mouse models have shown that artificial miRNAs can reduce mutant HTT, but evidence for their effectiveness and safety in larger animals is lacking. HD transgenic sheep express the full-length human HTT with 73 CAG repeats. AAV9 was used to deliver unilaterally to HD sheep striatum an artificial miRNA targeting exon 48 of the human HTT mRNA under control of two alternative promoters: U6 or CβA. The treatment reduced human mutant (m) HTT mRNA and protein 50-80% in the striatum at 1 and 6 months post injection. Silencing was detectable in both the caudate and putamen. Levels of endogenous sheep HTT protein were not affected. There was no significant loss of neurons labeled by DARPP32 or NeuN at 6 months after treatment, and Iba1-positive microglia were detected at control levels. It is concluded that safe and effective silencing of human mHTT protein can be achieved and sustained in a large-animal brain by direct delivery of an AAV carrying an artificial miRNA.
- MeSH
- Dependovirus genetika MeSH
- elektrolyty metabolismus MeSH
- genetické vektory metabolismus MeSH
- geneticky modifikovaná zvířata MeSH
- genom virový MeSH
- Huntingtonova nemoc genetika patologie MeSH
- imunoanalýza MeSH
- injekce MeSH
- játra patofyziologie MeSH
- ledviny patofyziologie MeSH
- lidé MeSH
- messenger RNA genetika metabolismus MeSH
- mikro RNA genetika metabolismus MeSH
- mikroglie metabolismus MeSH
- modely nemocí na zvířatech MeSH
- mutantní proteiny metabolismus MeSH
- neostriatum metabolismus MeSH
- neurony metabolismus MeSH
- ovce MeSH
- protein huntingtin metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Huntingtonova nemoc (HD) je neurodegenerativní porucha způsobená elongací CAG repetic v genu kódující protein huntingtin (Htt). U pacientů jsou v postižených tkáních přítomny vedle monomerní formy hlavně N‑koncové fragmenty, oligomery a polymery mutovaného huntingtinu (mtHtt), oproti tomu samotná monomerní forma mtHtt je exprimována v podstatě ve všech buňkách. Nejvíce postižené tkáně jsou bazální ganglia a mozková kůra. V této studii jsme analyzovali přítomnost N‑koncových fragmentů a oligomerů Htt v různých tkáních 24- a 36měsíčních transgenních (TgHD) miniprasat exprimujících N‑koncovou část lidského mutovaného huntingtinu a jejich zdravých sourozenců. Zjistili jsme, že mozková kůra a varlata na rozdíl od svalu a srdce TgHD miniprasat obsahují kromě monomerní formy i N‑koncové fragmenty a oligomerní smíry. Ve svalech z 36 měsíčních TgHD miniprasat však již začíná mírná fragmentace. Tato zjištění napodobují časnou progresi onemocnění u lidí, a proto miniprase poskytuje slibný model pro terapeutické testování HD. Klíčová slova: Huntingtonova nemoc – transgenní miniprasečí model – mutovaný huntingtin –proteinové fragmenty – oligomerní struktury Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy. Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů.
Huntington's disease (HD) is a neurodegenerative disorder caused by the the elongation of CAG triplet repeat in the gene encoding the huntingtin protein (Htt). In patients, in addition to the monomeric form of huntingtin, N‑terminal fragments, oligomers, and polymers are present mostly in the affected tissues, even though the mutated huntingtin (mtHtt) is expressed basically in all cells. The most affected tissues are basal ganglia and cerebral cortex. In this study we analyzed the presence of N‑terminal fragments and oligomers of Htt in different tissues of 24 and 36 months old experimental animals. This was done in our large animal model of HD, which uses transgenic (TgHD) minipigs expressing N‑terminal part of human mtHtt. Among all the tissues tested, we found cortex and testes to contain N‑terminal fragments as well as oligomeric smears in TgHD minipigs compared to wild type siblings. On the other hand, we did not detect any fragments or oligomers in muscle and heart of TgHD minipigs, only starting fragmentation in muscles of 36 months old animals. These findings mimic the early progression of the disease in humans, hence presents minipig as a promising model for therapeutic testing of HD.
- Klíčová slova
- mutovaný huntingtin, oligomerní struktury, proteinové fragmenty,
- MeSH
- geneticky modifikovaná zvířata MeSH
- Huntingtonova nemoc * metabolismus patologie MeSH
- konformace proteinů MeSH
- kosterní svaly metabolismus patologie MeSH
- miniaturní prasata MeSH
- modely u zvířat MeSH
- mozková kůra metabolismus patologie MeSH
- mutace MeSH
- prasata MeSH
- progrese nemoci MeSH
- proteiny nervové tkáně * genetika metabolismus MeSH
- testis metabolismus patologie MeSH
- western blotting MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- srovnávací studie MeSH
BACKGROUND: Although the highest expression of mutant huntingtin (mtHtt) was observed in the brain, its negative effects were also apparent in other tissues. Specifically, mtHtt impairs metabolic homeostasis and causes transcriptional dysregulation in adipose tissue. Adipogenic differentiation can be induced by the activation of two transcription factors: CCAAT/enhancer-binding protein alpha (CEBPα) and peroxisome proliferator-activated receptor gamma (PPARγ). These same transcription factors were found to be compromised in some tissues of Huntington's disease (HD) mouse models and in lymphocytes of HD patients. OBJECTIVE: This study investigated the adipogenic potential of mesenchymal stem cells (MSCs) derived from transgenic Huntington's disease (TgHD) minipigs expressing human mtHtt (1-548aa) containing 124 glutamines. Two differentiation conditions were used, employing PPARγ agonist rosiglitazone or indomethacin. METHODS: Bone marrow MSCs were isolated from TgHD and WT minipig siblings and compared by their cluster of differentiation using flow cytometry. Their adipogenic potential in vitro was analyzed using quantitative immunofluorescence and western blot analysis of transcription factors and adipogenic markers. RESULTS: Flow cytometry analysis did not reveal any significant difference between WT and TgHD MSCs. Nevertheless, following differentiation into adipocytes, the expression of CEBPα nuclear, PPARγ and adipogenic marker FABP4/AP2 were significantly lower in TgHD cells compared to WT cells. In addition, we proved both rosiglitazone and indomethacin to be efficient for adipogenic differentiation of porcine MSCs, with rosiglitazone showing a better adipogenic profile. CONCLUSIONS: We demonstrated a negative influence of mtHtt on adipogenic differentiation of porcine MSCs in vitro associated with compromised expression of adipogenic transcription factors.
- MeSH
- adipogeneze * MeSH
- buňky kostní dřeně cytologie MeSH
- geneticky modifikovaná zvířata genetika MeSH
- Huntingtonova nemoc genetika patologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- mezenchymální kmenové buňky cytologie MeSH
- prasata MeSH
- transkripční faktory genetika MeSH
- tukové buňky cytologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Huntingtonova nemoc (HN) je autozomálně dominantně dědičné neurodegenerativní onemocnění charakterizované motorickým deficitem, poruchami chování a kognitivních funkcí. Postihuje především mozek, přičemž změny související s HN byly nalezeny rovněž i v periferních tkáních. Některé z nich mohou být způsobeny přímou expresí mutovaného huntingtinu, jehož nejvyšší koncentrace byly nalezeny v mozku a varlatech pacientů s HN. V roce 2009 jsme vytvořili miniprasečí model HN (TgHD) exprimující N‑terminální (548aa) část lidského mutovaného huntingtinu kódujícího 124 CAG/CAA repetic. Na základě předchozích experimentů byla u TgHD kanců od 13. měsíce věku zjištěna zhoršená schopnost reprodukce a snížený počet spermií v ejakulátu. Cílem této studie bylo prokázat změny ve varlatech 24 měsíčních transgenních kanců (F2 generace in vivo) pomocí neinvazivní metody 31P magnetické rezonanční spektroskopie a provést imunohistochemickou analýzu TgHD spermií odebraných z F1 a F3 generace před projevením se klinických příznaků HN. Na základě vyšetření magnetickou rezonancí bylo zjištěno signifikantní snížení relativní koncentrace fosfodiesterů v testikulárním parenchymu TgHD kanců v porovnání s netransgenními jedinci (WT) stejné věkové kategorie. Rovněž imunohistochemická analýza spermií odebraných z TgHD a WT kanců odhalila výrazné anti‑polyQ specifické (klon 3B5H10) stejně tak i signifikantně zvýšené anti‑huntingtin (klon EPR5526) barvení v bičících transgenních spermiích v porovnání s netransgenními spermiemi. Na základě našich výsledků lze usuzovat, že lidský mutovaný huntingtin má negativní vliv na metabolizmus varlat a způsobuje zvýšený výskyt abnormalit spermií. Klíčová slova: Huntingtonova nemoc – varlata – spermie – miniprase – magnetická rezonanční spektroskopie Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy. Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů.
Huntington's disease (HD) is an inherited autosomal neurodegenerative disorder characterized by motor dysfunctions, behavioral and cognitive disturbances. It affects predominantly the brain, however, changes were found also in peripheral tissues. Some of these changes can result from direct expression of mutant huntingtin; its highest levels have been found in the brain and testes. In 2009 we established a minipig model of HD (TgHD) expressing N‑terminal (548aa) part of human mutated huntingtin encoded 124 CAG/CAA repeats. Previous research has revealed the presence of reduced fertility and fewer spermatozoa per ejaculate in TgHD boars started at 13 months of age. The aim of this study was to determine changes in the testes of 24 months old transgenic boars (F2 generation in vivo) using non‑invasive methodology of 31P magnetic resonance (MR) spectroscopy as well as to perform imunohistochemical analysis of TgHD sperm collected fromform F1 and F3 generation before HD onset. The results have shown significant reduction of relative phosphodiester concentration in testicular parenchyma of TgHD boars compared to wild type (WT) ones of the same ages. Moreover immunohistochemical analysis of sperm collected from TgHD and WT have revealed exclusive anti‑polyQ specific (clone 3B5H10) as well as significantly increased anti‑huntingtin (clone EPR5526) staining in transgenic spermatozoa tails in comparison with WT counterparts. Thus, our results are suggestive of the negative impact of human mutated huntingtin on testes metabolism as well as sperm abnormalities.
- Klíčová slova
- huntingtin,
- MeSH
- geneticky modifikovaná zvířata MeSH
- Huntingtonova nemoc * genetika metabolismus MeSH
- imunohistochemie statistika a číselné údaje MeSH
- magnetická rezonanční spektroskopie statistika a číselné údaje MeSH
- miniaturní prasata MeSH
- mutace MeSH
- prasata MeSH
- proteiny nervové tkáně genetika metabolismus MeSH
- spermie * chemie MeSH
- testis * metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Huntington disease (HD) is the most frequent monogenetic neurodegenerative disease and can be unequivocally diagnosed even in the preclinical stage, at least in all individuals in whom the CAG expansion mutation in the huntingtin gene (HTT) is in the range of full penetrance. Therefore, important preconditions for an intervention early in the disease process are met, rendering modification of the course of the disease in a clinically meaningful way possible. In this respect, HD can be viewed as a model disorder for exploring neuroprotective treatment approaches. In the past emphasis was placed on the compensation of a suspected neurotransmitter deficit (GABA) analogous to Parkinson's disease and on classical neuroprotective strategies to influence hypothetical common pathways in neurodegenerative diseases (e.g., excitotoxicity, mitochondrial dysfunction, oxidative stress). With the discovery of the causative HTT mutation in 1993, therapeutic research increasingly focused on intervening as proximally as possible in the chain of pathophysiological events. Currently, an important point of intervention is the HTT mRNA with the aim of reducing the continued production of mutant huntingtin gene products and thus relieving the body of their detrimental actions. To this end, various treatment modalities (single-stranded DNA and RNA, divalent RNA and zinc finger repressor complexes, orally available splice modulators) were developed and are currently in clinical trials (phases I-III) or in late stages of preclinical development. In addition, there is the notion that it may be possible to modify the length of the somatically unstable CAG mutation, i.e. its increase in the brain during the lifetime, thereby slowing the progression of HD.
