Alzheimer’s Disease: An Updated Overview of Its Genetics

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(4), С. 3754 - 3754

Опубликована: Фев. 13, 2023

Alzheimer’s disease (AD) is the most common neurodegenerative in world. It classified as familial and sporadic. The dominant or autosomal presentation represents 1–5% of total number cases. categorized early onset (EOAD; <65 years age) presents genetic mutations presenilin 1 (PSEN1), 2 (PSEN2), Amyloid precursor protein (APP). Sporadic AD 95% cases late-onset (LOAD), occurring patients older than 65 age. Several risk factors have been identified sporadic AD; aging main one. Nonetheless, multiple genes associated with different neuropathological events involved LOAD, such pathological processing beta (Aβ) peptide Tau protein, well synaptic mitochondrial dysfunctions, neurovascular alterations, oxidative stress, neuroinflammation, among others. Interestingly, using genome-wide association study (GWAS) technology, many polymorphisms LOAD identified. This review aims to analyze new findings that are closely related pathophysiology AD. Likewise, it analyzes date through GWAS a high low developing this neurodegeneration. Understanding variability will allow for identification biomarkers opportune therapeutic targets

Язык: Английский

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A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models

Nature Biotechnology, Год журнала: 2024, Номер unknown

Опубликована: Март 8, 2024

Abstract Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease with a high mortality rate. Putative drug targets in IPF have failed to translate into effective therapies at the clinical level. We identify TRAF2- and NCK-interacting kinase (TNIK) as anti-fibrotic target using predictive artificial intelligence (AI) approach. Using AI-driven methodology, we generated INS018_055, small-molecule TNIK inhibitor, which exhibits desirable drug-like properties activity across different organs vivo through oral, inhaled or topical administration. INS018_055 possesses anti-inflammatory effects addition its profile, validated multiple studies. Its safety tolerability well pharmacokinetics were randomized, double-blinded, placebo-controlled phase I trial (NCT05154240) involving 78 healthy participants. A separate China, CTR20221542, also demonstrated comparable pharmacokinetic profiles. This work was completed roughly 18 months from discovery preclinical candidate nomination demonstrates capabilities of our generative drug-discovery pipeline.

Язык: Английский

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Targeting synapse function and loss for treatment of neurodegenerative diseases

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 23(1), С. 23 - 42

Опубликована: Ноя. 27, 2023

Язык: Английский

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MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo

Cell stem cell, Год журнала: 2019, Номер 24(4), С. 579 - 591.e12

Опубликована: Март 7, 2019

Heart disease is a paramount cause of global death and disability. Although cardiomyocyte plays causal role its suppression would be logical, no clinical counter-measures target the responsible intracellular pathways. Therapeutic progress has been hampered by lack preclinical human validation. Mitogen-activated protein kinase kinase-4 (MAP4K4) activated in failing hearts relevant rodent models. Using induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) MAP4K4 gene silencing, we demonstrate that induced oxidative stress requires MAP4K4. Consequently, devised small-molecule inhibitor, DMX-5804, rescues cell survival, mitochondrial function, calcium cycling hiPSC-CMs. As proof principle drug discovery hiPSC-CMs may predict efficacy vivo, DMX-5804 reduces ischemia-reperfusion injury mice more than 50%. We implicate as well-posed toward suppressing cardiac highlight utility to enhance survival.

Язык: Английский

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Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Июль 3, 2020

Abstract Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of variant accessibility gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear characteristic SLE. Of ~400 potential regulatory identified, 90% exhibit proximity to distant 1D genome sequence, including loop regulate canonical TFH BCL6 CXCR5 as confirmed editing. ‘variant-to-gene’ also implicate no known role TFH/SLE disease biology, kinases HIPK1 MINK1. Targeting these inhibits production IL-21, cytokine crucial class-switched B antibodies. These offer mechanistic insight into SLE-associated architecture genome.

Язык: Английский

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Improved modeling of human AD with an automated culturing platform for iPSC neurons, astrocytes and microglia

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Сен. 1, 2021

Advancement in human induced pluripotent stem cell (iPSC) neuron and microglial differentiation protocols allow for disease modeling using physiologically relevant cells. However, iPSC culturing have posed challenges to maintaining consistency. Here, we generated an automated, consistent, long-term platform of neurons, astrocytes, microglia. Using this a AD model derived cells, which showed signs Aβ plaques, dystrophic neurites around synapse loss, dendrite retraction, axon fragmentation, phospho-Tau induction, neuronal death one model. We that the microglia internalized compacted generate surround thereby conferring some neuroprotection. investigated mechanism action anti-Aβ antibodies protection found they protected neurons from these pathologies were most effective before pTau induction. Taken together, results suggest can facilitate target discovery drug development efforts.

Язык: Английский

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A 5′-tRNA halve, tiRNA-Gly promotes cell proliferation and migration via binding to RBM17 and inducing alternative splicing in papillary thyroid cancer

Journal of Experimental & Clinical Cancer Research, Год журнала: 2021, Номер 40(1)

Опубликована: Июль 5, 2021

Abstract Background tRNA-derived small noncoding RNAs (sncRNAs) are mainly categorized into tRNA halves (tiRNAs) and fragments (tRFs). Biological functions of tiRNAs in human solid tumor attracting more attention, but researches concerning the mechanisms tiRNAs-mediated tumorigenesis rarely. The direct regulatory relationship between splicing-related proteins remain elusive. Methods Papillary thyroid carcinoma (PTC) associated were screened by deep sequencing validated qRT-PCR Northern Blot PTC tissues. biological function assessed cell counting kit, transwells subcutaneous transplantation nude mice. For mechanistic study, pull-down, RNA immunoprecipitation, Western Blot, Immunofluorescence, Immunohistochemical staining performed. Results Herein, we have identified a 33 nt tiRNA-Gly significantly increases papillary cancer based on tRFs & sequencing. ectopic expression promotes proliferation migration, whereas down-regulation exhibits reverse effects. Mechanistic investigations reveal directly bind UHM domain RNA-binding protein RBM17. interaction with could translocate RBM17 from cytoplasm nucleus. In addition, via inhibiting its degradation ubiquitin/proteasome-dependent way. Moreover, level high-expressing tissues is upregulated. vivo mouse model shows that suppression decreases expression. Importantly, can induce exon 16 splicing MAP4K4 mRNA leading to phosphorylation downstream signaling pathway, which dependent. Conclusions Our study firstly illustrates display oncogenic effect RBM17-mediated alternative splicing. This fully novel broadens our understanding molecular mechanism fragment cells binding play role

Язык: Английский

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Histone lactylation-derived LINC01127 promotes the self-renewal of glioblastoma stem cells via the cis-regulating the MAP4K4 to activate JNK pathway

Cancer Letters, Год журнала: 2023, Номер 579, С. 216467 - 216467

Опубликована: Окт. 29, 2023

Язык: Английский

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The response of Dual-leucine zipper kinase (DLK) to nocodazole: Evidence for a homeostatic cytoskeletal repair mechanism

PLoS ONE, Год журнала: 2024, Номер 19(4), С. e0300539 - e0300539

Опубликована: Апрель 4, 2024

Genetic and pharmacological perturbation of the cytoskeleton enhances regenerative potential neurons. This response requires Dual-leucine Zipper Kinase (DLK), a neuronal stress sensor that is central regulator axon regeneration degeneration. The damage repair aspects this are reminiscent other cellular homeostatic systems, suggesting cytoskeletal exists. In study, we propose framework for understanding DLK mediated homeostasis. We demonstrate low dose nocodazole treatment activates signaling. Activation signaling results in DLK-dependent transcriptional signature, which identify through RNA-seq. signature includes genes likely to attenuate while simultaneously inducing actin regulating genes. alterations including actin-based morphological changes axon. These consistent with model disruption neuron induces mechanism, term Cytoskeletal Stress Response (CSR) pathway.

Язык: Английский

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An axonal stress response pathway: degenerative and regenerative signaling by DLK

Current Opinion in Neurobiology, Год журнала: 2018, Номер 53, С. 110 - 119

Опубликована: Июль 24, 2018

Язык: Английский

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