Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 26, 2024

The induced pluripotent stem cell (iPSC) technology has transformed in vitro research and holds great promise to advance regenerative medicine. iPSCs have the capacity for an almost unlimited expansion, are amenable genetic engineering, can be differentiated into most somatic types. been widely applied model human development diseases, perform drug screening, develop therapies. In this review, we outline key developments iPSC field highlight immense versatility of modeling therapeutic applications. We begin by discussing pivotal discoveries that revealed potential a nucleus reprogramming led successful generation iPSCs. consider molecular mechanisms dynamics as well numerous methods available induce pluripotency. Subsequently, discuss various iPSC-based cellular models, from mono-cultures single type complex three-dimensional organoids, how these models elucidate diseases. use examples neurological disorders, coronavirus disease 2019 (COVID-19), cancer diversity disease-specific phenotypes modeled using iPSC-derived cells. also used high-throughput screening toxicity studies. Finally, process developing autologous allogeneic therapies their alleviate

Language: Английский

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Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

Cells, Journal Year: 2024, Volume and Issue: 13(6), P. 511 - 511

Published: March 14, 2024

Neuroinflammatory and neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s (PD), traumatic brain injury (TBI) Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions these pathogeneses is currently not clearly understood. These show dysregulated inflammatory responses, activation neurons, glial cells, neurovascular unit damage associated with excessive release proinflammatory cytokines, chemokines, neurotoxic mediators, infiltration peripheral immune cells into brain, as well entry mediators through damaged endothelial blood–brain barrier tight junction proteins. Activation leads to many molecules that cause neuroinflammation neurodegeneration. Gulf War Illness (GWI) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) also dysfunctions. Currently, there no effective disease-modifying therapeutic options available for diseases. Human induced pluripotent stem cell (iPSC)-derived astrocytes, microglia, pericytes used models drug discovery. This review highlights certain recent trends in neuroinflammatory responses iPSC-derived applications

Language: Английский

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A model of human neural networks reveals NPTX2 pathology in ALS and FTLD

Nature, Journal Year: 2024, Volume and Issue: 626(8001), P. 1073 - 1083

Published: Feb. 14, 2024

Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating age-dependent diseases. Such systems are particularly needed TDP-43 proteinopathies

Language: Английский

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C-terminal amides mark proteins for degradation via SCF–FBXO31

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

During normal cellular homeostasis, unfolded and mislocalized proteins are recognized removed, preventing the build-up of toxic byproducts1. When protein homeostasis is perturbed during ageing, neurodegeneration or stress, can accumulate several forms chemical damage through reactive metabolites2,3. Such modifications have been proposed to trigger selective removal chemically marked proteins3-6; however, identifying that sufficient induce degradation has remained challenging. Here, using a semi-synthetic biology approach coupled assays, we found C-terminal amide-bearing (CTAPs) rapidly cleared from human cells. A CRISPR screen identified FBXO31 as reader amides. substrate receptor for SKP1-CUL1-F-box (SCF) ubiquitin ligase SCF-FBXO31, which ubiquitylates CTAPs subsequent proteasomal degradation. conserved binding pocket enables bind almost any peptide bearing an amide while retaining exquisite selectivity over non-modified clients. This mechanism facilitates turnover endogenous formed after oxidative stress. dominant mutation in neurodevelopmental disorders reverses CTAP recognition, such non-amidated neosubstrates now degraded becomes markedly toxic. We propose may represent vanguard largely unexplored class modified amino acid degrons could provide general strategy yet broad surveillance damaged proteins.

Language: Английский

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Current State and Future Directions in the Diagnosis of Amyotrophic Lateral Sclerosis

Cells, Journal Year: 2023, Volume and Issue: 12(5), P. 736 - 736

Published: Feb. 24, 2023

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness all voluntary muscles eventual respiratory failure. Non-motor symptoms, such as cognitive behavioral changes, frequently occur over the course disease. Considering its poor prognosis with median survival time 2 to 4 years limited causal treatment options, an early diagnosis ALS plays essential role. In past, has primarily been determined clinical findings supported electrophysiological laboratory measurements. To increase diagnostic accuracy, reduce delay, optimize stratification trials provide quantitative monitoring progression responsivity, research on disease-specific feasible fluid biomarkers, neurofilaments, intensely pursued. Advances imaging techniques have additionally yielded benefits. Growing perception greater availability genetic testing facilitate identification pathogenic ALS-related gene mutations, predictive access novel therapeutic agents addressing disease-modified therapies before advent first symptoms. Lately, personalized prediction models proposed offer more detailed disclosure for patient. this review, established procedures future directions diagnostics are summarized serve practical guideline improve pathway burdensome

Language: Английский

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Multiomics and machine-learning identify novel transcriptional and mutational signatures in amyotrophic lateral sclerosis

Brain, Journal Year: 2023, Volume and Issue: 146(9), P. 3770 - 3782

Published: March 6, 2023

Abstract Amyotrophic lateral sclerosis is a fatal and incurable neurodegenerative disease that mainly affects the neurons of motor system. Despite increasing understanding its genetic components, their biological meanings are still poorly understood. Indeed, it not clear to which extent pathological features associated with amyotrophic commonly shared by different genes causally linked this disorder. To address point, we combined multiomics analysis covering transcriptional, epigenetic mutational aspects heterogenous human induced pluripotent stem cell-derived C9orf72-, TARDBP-, SOD1- FUS-mutant as well datasets from patients’ biopsies. We identified common signature, converging towards increased stress synaptic abnormalities, reflects unifying transcriptional program in despite specific profiles due underlying pathogenic gene. In addition, whole genome bisulphite sequencing altered gene expression observed mutant cells methylation profile, highlighting deep alterations part abnormal signatures sclerosis. then applied multi-layer machine-learning integrate publicly available blood spinal cord transcriptomes found statistically significant correlation between top predictor sets, were significantly enriched toll-like receptor signalling. Notably, overrepresentation term also correlated signature neurons, novel insights into marker tissue-independent manner. Finally, using combination learning, generated first for defined genomic profile disease, ageing signatures, hinting at age major player This work describes innovative methodological approaches identification through provides knowledge on convergencies defining

Language: Английский

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Focusing on mitochondria in the brain: from biology to therapeutics

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: April 17, 2024

Abstract Mitochondria have multiple functions such as supplying energy, regulating the redox status, and producing proteins encoded by an independent genome. They are closely related to physiology pathology of many organs tissues, among which brain is particularly prominent. The demands 20% resting metabolic rate holds highly active mitochondrial activities. Considerable research shows that mitochondria function, while defects induce or exacerbate in brain. In this review, we provide comprehensive advances biology involved functions, well mitochondria-dependent cellular events pathology. Furthermore, various perspectives explored better identify roles neurological diseases neurophenotypes diseases. Finally, therapies discussed. Mitochondrial-targeting therapeutics showing great potentials treatment

Language: Английский

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Nuclear pore dysfunction and disease: a complex opportunity

Nucleus, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 21, 2024

The separation of genetic material from bulk cytoplasm has enabled the evolution increasingly complex organisms, allowing for development sophisticated forms life. However, this complexity created new categories dysfunction, including those related to movement between cellular compartments. In eukaryotic cells, nucleocytoplasmic trafficking is a fundamental biological process, and cumulative disruptions nuclear integrity transport are detrimental cell survival. This particularly true in post-mitotic neurons, where pore injury errors strongly associated with neurodegenerative disease. review, we summarize current understanding biology physiological pathological contexts discuss potential therapeutic approaches addressing dysfunctional transport.

Language: Английский

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The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 3, 2024

Abstract Lipid changes in the brain have been implicated many neurodegenerative diseases including Alzheimer’s Disease (AD), Parkinson’s disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named Neurolipid Atlas, that pre-populated with novel human, mouse isogenic induced pluripotent stem cell (iPSC)-derived lipidomics for different diseases. We show iPSC-derived neurons, microglia astrocytes display distinct lipid profiles recapitulate vivo lipotypes. Leveraging multiple datasets, AD risk gene ApoE4 drives cholesterol ester (CE) accumulation human recapitulating CE measured brain. Multi-omic interrogation of revealed plays major role astrocyte interferon-dependent pathways such as immunoproteasome histocompatibility complex (MHC) class I antigen presentation. through enhanced esterification suppresses immune activation astrocytes. Our commons, available at neurolipidatlas.com, provides user-friendly tool knowledge base better understanding dyshomeostasis

Language: Английский

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A toxic gain-of-function mechanism in C9orf72 ALS impairs the autophagy-lysosome pathway in neurons

Acta Neuropathologica Communications, Journal Year: 2023, Volume and Issue: 11(1)

Published: Sept. 18, 2023

Abstract Background Motor neurons (MNs), which are primarily affected in amyotrophic lateral sclerosis (ALS), a specialized type of that long and non-dividing. Given their unique structure, these cells heavily rely on transport organelles along axons the process autophagy to maintain cellular homeostasis. It has been shown disruption pathway is sufficient cause progressive neurodegeneration defects have associated with various subtypes ALS, including those caused by hexanucleotide repeat expansions C9orf72 gene. A more comprehensive understanding dysfunctional mechanisms will help rationalize design potent selective therapies for -ALS. Methods In this study, we used induced pluripotent stem cell (iPSC)-derived MNs from -ALS patients isogenic control lines identify underlying causing dysregulations autophagy-lysosome pathway. Additionally, ascertain potential impact loss-of-function autophagic defects, characterized observed phenotypes knockout iPSC line (C9-KO). Results Despite evident presence dysfunctions several aspects pathway, such as disrupted lysosomal homeostasis, abnormal lysosome morphology, inhibition flux, accumulation p62 MNs, were surprised find had minimal influence phenotypes. Instead, impairment endosome maturation result loss-of-function. our study shed light pathological -ALS, detected an increased TBK1 phosphorylation at S172 derived ALS patients. Conclusions Our data provides further insight into involvement strongly indicate mainly due toxic gain-of-function

Language: Английский

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