Russian Journal of Bioorganic Chemistry, Год журнала: 2023, Номер unknown
Опубликована: Дек. 1, 2023
Язык: Английский
The American Journal of Human Genetics, Год журнала: 2024, Номер 111(6), С. 1165 - 1183
Опубликована: Май 14, 2024
The pathological huntingtin (HTT) trinucleotide repeat underlying Huntington disease (HD) continues to expand throughout life. Repeat length correlates both with earlier age at onset (AaO) and faster progression, making slowing its expansion an attractive therapeutic approach. Genome-wide association studies have identified candidate variants associated altered AaO many found in DNA mismatch repair (MMR)-associated genes. We examine whether lowering expression of these genes affects the rate human ex vivo models using HD iPSCs iPSC-derived striatal medium spiny neuron-enriched cultures. generated a stable CRISPR interference iPSC line which we can specifically efficiently lower gene from donor carrying over 125 CAG repeats. Lowering each member MMR complexes MutS (MSH2, MSH3, MSH6), MutL (MLH1, PMS1, PMS2, MLH3), LIG1 resulted characteristic deficiencies. Reduced MSH2, MLH1 slowed largest degree, while either or MLH3 it lesser degree. These effects were recapitulated cultures where factor was lowered. CRISPRi-mediated key levels feasibly achievable by current approaches able effectively slow HTT tract. highlight members family as potential targets pathogenic aim delay progression potentially other disorders exhibiting somatic instability.
Язык: Английский
Процитировано
10
Metabolites, Год журнала: 2025, Номер 15(1), С. 10 - 10
Опубликована: Янв. 2, 2025
Huntington's disease (HD) is a multifaceted neurological disorder characterized by the progressive deterioration of motor, cognitive, and psychiatric functions. Despite limited understanding its pathogenesis, research has implicated abnormal trinucleotide cytosine-adenine-guanine CAG repeat expansion in huntingtin gene (HTT) as critical factor. The development innovative strategies imperative for early detection predictive biomarkers, enabling timely intervention mitigating irreversible cellular damage. Lipidomics, comprehensive analytical approach, emerged an indispensable tool systematically characterizing lipid profiles elucidating their role pathology. A MedLine search was performed to identify studies that use lipidomics characterization HD. Search terms included "Huntington disease"; "lipidomics"; "biomarker discovery"; "NMR"; "Mass spectrometry". This review highlights significance HD diagnosis treatment, exploring changes brain lipids Recent breakthroughs techniques, particularly mass spectrometry NMR spectroscopy, have revolutionized research, researchers gain deeper insights into complex lipidome brain. broad spectrum alterations vital precise diagnostic evaluation effective management. integration with artificial intelligence interdisciplinary collaboration holds promise addressing clinical variability
Язык: Английский
Процитировано
1
Advances in pharmacology, Год журнала: 2025, Номер unknown, С. 1 - 26
Опубликована: Янв. 1, 2025
Язык: Английский
Процитировано
1
Cells, Год журнала: 2025, Номер 14(5), С. 347 - 347
Опубликована: Фев. 27, 2025
Neurodegenerative diseases encompass a number of very heterogeneous disorders, primarily characterized by neuronal loss and concomitant decline in neurological function. Examples this type clinical condition are Alzheimer's Disease, Parkinson's Huntington's Disease Amyotrophic Lateral Sclerosis. Age has been identified as major risk the etiology these which explains their increased incidence developed countries. Unfortunately, despite continued intensive efforts, no cure yet found for any diseases; reliable markers that allow an early diagnosis disease identification key molecular events leading to onset progression lacking. Altered adult neurogenesis appears precede appearance severe symptoms. Given scarcity human samples considerable differences with model species, increasingly complex stem-cell-based models being developed. These shedding light on alterations contribute development, facilitating new targets providing screening platform testing candidate drugs. Moreover, secretome other promising features cell types explored, use them replacement cells high plasticity or co-adjuvant therapy combinatorial treatments.
Язык: Английский
Процитировано
0
Neurobiology of Disease, Год журнала: 2025, Номер unknown, С. 106914 - 106914
Опубликована: Апрель 1, 2025
Huntington's Disease (HD) is caused by a CAG repeat expansion in the gene encoding Huntingtin (HTT). While normal HTT function appears impacted mutation, specific pathways unique to versus loss of are unclear. To understand impact expansion, we evaluated biological signatures knockout (HTT KO) those that occur from applying multi-omics, live cell imaging, survival analysis and novel feature- based pipeline study cortical neurons (eCNs) derived an isogenic human embryonic stem series (RUES2). KO influence developmental trajectories eCNs, with opposing effects on growth. Network analyses differentially expressed genes proteins associated enriched epigenetic motifs identified subnetworks common include neuronal differentiation, cycle regulation, mechanisms related transcriptional repression may represent gain-of-function cannot be explained alone. A combination dominant loss-of-function likely involved aberrant neurodevelopmental neurodegenerative features HD can help inform therapeutic strategies.
Язык: Английский
Процитировано
0
International Journal of Biological Sciences, Год журнала: 2024, Номер 20(10), С. 3710 - 3724
Опубликована: Янв. 1, 2024
Lipid homeostasis is crucial for proper cellular and systemic functions.A growing number of studies confirm the importance lipid in diabetic kidney disease (DKD).Lipotoxicity caused by imbalance renal can further exasperate injury.Large deposits droplet accumulation are present kidneys DKD patients.Autophagy plays a critical role involved regulation content.Inhibition or reduction autophagy lead to accumulation, which turn affects autophagy.Lipophagy selectively recognizes degrades lipids helps regulate metabolism maintain intracellular homeostasis.Therefore, we provide systematic review fatty acid, cholesterol, sphingolipid metabolism, discuss responses different intrinsic cells imbalances homeostasis.Finally, mechanism autophagy, especially lipophagy, maintains support development new drugs targeting homeostasis.
Язык: Английский
Процитировано
3
Neurobiology of Disease, Год журнала: 2023, Номер 190, С. 106367 - 106367
Опубликована: Ноя. 30, 2023
X-linked dystonia-parkinsonism (XDP) is a rare neurodegenerative disease endemic to the Philippines. The genetic cause for XDP an insertion of SINE-VNTR-Alu (SVA)-type retrotransposon within intron 32 TATA-binding protein associated factor 1 (TAF1) that causes alteration TAF1 splicing, partial retention, and decreased transcription. Although expressed in all organs, medium spiny neurons (MSNs) striatum are one cell types most affected XDP. To define how mutations gene lead MSN vulnerability, we carried out proteomic analysis human patient-derived neural stem cells (NSCs) MSNs derived from induced pluripotent cells. NSCs were grown parallel subjected quantitative data-independent acquisition mode on Orbitrap Eclipse Tribrid mass spectrometer. Subsequent functional enrichment demonstrated disease-related pathways, such as Huntington's disease, spinocerebellar ataxia, cellular senescence, mitochondrial function RNA binding metabolism, highly represented. We used weighted coexpression network (WGCNA) NSC data set uncover disease-driving modules. Three modules significantly correlated with genotype when compared non-affected control enriched DNA helicase nuclear chromatin assembly, disassembly, location mRNA processing. Consistent aberrant processing, found splicing retention MSN. also identified top transcription factors, along YY1, ATF2, USF1 MYC. Notably, YY1 has been implicated forms dystonia. Overall, our constitutes valuable resource understand mechanisms relevant dysregulation identify new therapeutic targets
Язык: Английский
Процитировано
5
Neurobiology of Disease, Год журнала: 2023, Номер 190, С. 106368 - 106368
Опубликована: Ноя. 29, 2023
In Huntington disease, cellular toxicity is particularly caused by toxic protein fragments generated from the mutant huntingtin (HTT) protein. By modifying HTT protein, we aim to reduce proteolytic cleavage and ameliorate consequences of without lowering total levels. To that end, use an antisense oligonucleotide (AON) targets pre-mRNA induces partial skipping exon 12, which contains critical caspase-6 site. Here, show AON-treatment can partially restore phenotype YAC128 mice, a mouse model expressing full-length human gene including 128 CAG-repeats. Wild-type mice were treated intracerebroventricularly with AON12.1, scrambled AON or vehicle starting at 6 months age followed up 12 age, when MRI was performed sacrificed. AON12.1 treatment induced around 40% skip modification. The on body weight activity, but not rotarod, restored treatment. Genes differentially expressed in striatum changed toward wild-type levels striatal volume preserved upon However, also showed restorative effect expression appeared generally increase brain volume.
Язык: Английский
Процитировано
4
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Май 20, 2024
Abstract Huntington’s disease (HD) is a fatal neurodegenerative disorder that caused by the expansion of CAG repeats in HTT gene, which results long polyglutamine (polyQ) tract huntingtin protein (HTT). In this study, we searched for networks deregulated RNAs contribute to initial transcriptional changes HD neuronal cells and HTT-deficient cells. We used RNA-seq (including small RNA sequencing) analyze set isogenic, human induced pluripotent stem cell (iPSC)-derived neural (NSCs); observed numerous gene expression substantial dysregulation miRNA -knockout ( -KO) lines. The was upregulated both -KO enriched genes are associated with DNA binding regulation transcription. For these models, confirmed upregulation transcription factors (TFs) TWIST1, SIX1, TBX1, TBX15, MSX2, MEOX2 FOXD1 NSCs medium spiny neuron (MSN)-like Moreover, identified miRNAs were consistently MSN-like cells, including miR-214, miR-199, miR-9. suggest function network regulates TWIST1 via regulatory feed-forward loop (FFL) HD. Additionally, reported selected TFs tended progressively change during differentiation what not model. Based on comparing lines, propose early deregulation largely loss function.
Язык: Английский
Процитировано
1
Neurobiology of Disease, Год журнала: 2024, Номер 200, С. 106630 - 106630
Опубликована: Авг. 5, 2024
Despite growing descriptions of wild-type Huntingtin (wt-HTT) roles in both adult brain function and, more recently, development, several clinical trials are exploring HTT-lowering approaches that target wt-HTT and the mutant isoform (mut-HTT) responsible for Huntington's disease (HD). This non-selective targeting is based on autosomal dominant inheritance HD, supporting idea mut-HTT exerts its harmful effects through a toxic gain-of-function or dominant-negative mechanism. However, precise amount needed healthy neurons adults during development remains unclear. In this study, we address question by examining how loss affects human neuronal network formation, synaptic maturation, homeostasis vitro. Our findings establish role maturation dendritic arborization acquisition network-wide synchronized activity cortical networks modeled Interestingly, synchronization defects only became apparent when than two-thirds protein was depleted. study underscores critical need to precisely understand health. It also emphasizes potential risks excessive associated with therapeutic wt- isoforms HD patients.
Язык: Английский
Процитировано
1