Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer’s disease DOI Creative Commons
Phoebe Valdes, Andrew B. Caldwell, Qing Liu

et al.

Research Square (Research Square), Journal Year: 2022, Volume and Issue: unknown

Published: Dec. 9, 2022

Abstract Background Mutations in PSEN1, PSEN2, and APP can lead to Alzheimer’s disease (AD) with an early age at onset (AAO) hallmark progressive cognitive decline. These mutations are highly penetrant. Although PSEN1 more common usually have earlier AAO, certain cause a later similar PSEN2 mutations. We sought determine whether endotypes exist across these relatively late AAO. Methods generated hiPSC-derived neurons from patients harboring autosomal-dominant, familial (FAD) documented around 55 years: PSEN1A79V, PSEN2N141I, APPV717I. carried out RNA-seq ATAC-seq mechanistically characterize the gene expression chromatin accessibility changes, respectively. Differential analysis, enrichment TF activity identification, co-expression module detection were performed for RNA-seq. peak analysis annotation, motif footprinting differential accessibility, functional ATAC-seq. This approach allowed us identify correlation between associated key endotypes. Results Using multiomics approach, we all three FAD genes: dedifferentiation of mature neuron less differentiated quasi-neuron state, dysregulation synaptic signaling, repression mitochondrial function metabolism, inflammation. The integrativeanalysis ascertain master transcriptional regulators endotypes, including REST, ASCL1, ZIC family members (activation), as well NRF1 (repression). Conclusions Our findings regulatory changes within However, severity often differs both magnitude direction. overarching link genes is reversion less-differentiated state. mechanisms described offer potential targets therapeutic interventions.

Language: Английский

Brain Plasticity and Cell Competition: Immediate Early Genes Are the Focus DOI Creative Commons
П. П. Трегуб, Yulia K. Komleva,

Maria V. Kukla

et al.

Cells, Journal Year: 2025, Volume and Issue: 14(2), P. 143 - 143

Published: Jan. 19, 2025

Brain plasticity is at the basis of many cognitive functions, including learning and memory. It includes several mechanisms synaptic extrasynaptic changes, neurogenesis, formation elimination synapses. The transmission involves expression immediate early genes (IEGs) that regulate neuronal activity, thereby supporting In addition, IEGs are involved in regulation brain cells’ metabolism, proliferation, survival, establishment multicellular ensembles, and, presumably, cell competition tissue. this review, we analyze current understanding role (c-Fos, c-Myc, Arg3.1/Arc) controlling physiological pathological conditions, aging neurodegeneration. This work might inspire new gene therapy strategies targeting to plasticity, potentially prevent or mitigate neurodegenerative diseases.

Language: Английский

Citations

2
Polyploidy as a Fundamental Phenomenon in Evolution, Development, Adaptation and Diseases DOI Open Access
Olga V. Anatskaya, Alexander E. Vinogradov

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(7), P. 3542 - 3542

Published: March 24, 2022

DNA replication during cell proliferation is ‘vertical’ copying, which reproduces an initial amount of genetic information. Polyploidy, results from whole-genome duplication, a fundamental complement to vertical copying. Both organismal and polyploidy can emerge via premature cycle exit or cell-cell fusion, the latter giving rise polyploid hybrid organisms epigenetic hybrids somatic cells. Polyploidy-related increase in biological plasticity, adaptation, stress resistance manifests evolution, development, regeneration, aging, oncogenesis, cardiovascular diseases. Despite prevalence nature importance for medicine, agri- aquaculture, processes mechanisms underlying these features largely remain unknown. The evolutionarily conserved include activation transcription, response stress, damage hypoxia, induction programs morphogenesis, unicellularity, longevity, suggesting that common confer adaptive viability, cells organisms. By increasing polyploidization provide survival under stressful conditions where diploid cannot survive. However, it occurs at expense specific function, thus promoting developmental programming adult diseases risk cancer. Notably, genes arising evolutionary are heavily involved cancer other Ploidy-related changes gene expression presumably originate chromatin modifications derepression bivalent genes. provided evidence elucidates role carcinogenesis, may contribute development new strategies regeneration preventing

Language: Английский

Citations

52
Neuronal cell cycle reentry events in the aging brain are more prevalent in neurodegeneration and lead to cellular senescence DOI Creative Commons
Deng Wu, Jacquelyne Ka‐Li Sun, Hei‐Man Chow

et al.

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(4), P. e3002559 - e3002559

Published: April 23, 2024

Increasing evidence indicates that terminally differentiated neurons in the brain may recommit to a cell cycle-like process during neuronal aging and under disease conditions. Because of rare existence random localization these cells brain, their molecular profiles disease-specific heterogeneities remain unclear. Through bioinformatics approach allows integrated analyses multiple single-nucleus transcriptome datasets from human samples, populations were identified selected for further characterization. Our indicated cycle-related events occur predominantly excitatory cellular senescence is likely immediate terminal fate. Quantitatively, number cycle re-engaging senescent decreased normal process, but context late-onset Alzheimer's (AD), accumulate instead. Transcriptomic profiling suggested differences tied early stage revealing presented more proinflammatory, metabolically deregulated, pathology-associated signatures disease-affected brains. Similarly, general features also observed subpopulation dopaminergic Parkinson's (PD)-Lewy body dementia (LBD) model. An extended analysis conducted mouse model validated ability this determine robust relationship between processes cross-species setting.

Language: Английский

Citations

13
Retrotransposons as a Source of DNA Damage in Neurodegeneration DOI Creative Commons

Eugénie Pezé-Heidsieck,

Tom Bonnifet,

Rania Znaidi

et al.

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 13

Published: Jan. 4, 2022

The etiology of aging-associated neurodegenerative diseases (NDs), such as Parkinson's disease (PD) and Alzheimer's (AD), still remains elusive no curative treatment is available. Age the major risk factor for PD AD, but molecular link between aging neurodegeneration not fully understood. Aging defined by several hallmarks, some which partially overlap with pathways implicated in NDs. Recent evidence suggests that epigenetic alterations can lead to derepression LINE-1 (Long Interspersed Element-1) family transposable elements (TEs) this might have important implications pathogenesis Almost half human DNA composed repetitive sequences derived from TEs TE mobility participated shaping mammalian genomes during evolution. Although most are mutated longer mobile, more than 100 retained their full coding potential humans thus retrotransposition competent. Uncontrolled activation has now been reported various models diseased brain tissues. We will discuss review contribution inducing damage genomic instability, emerging pathological features represent an neurodegeneration, a target urgently needed novel therapeutic disease-modifying interventions.

Language: Английский

Citations

29
Polyploidy and Myc Proto-Oncogenes Promote Stress Adaptation via Epigenetic Plasticity and Gene Regulatory Network Rewiring DOI Open Access
Olga V. Anatskaya, Alexander E. Vinogradov

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(17), P. 9691 - 9691

Published: Aug. 26, 2022

Polyploid cells demonstrate biological plasticity and stress adaptation in evolution; development; pathologies, including cardiovascular diseases, neurodegeneration, cancer. The nature of ploidy-related advantages is still not completely understood. Here, we summarize the literature on molecular mechanisms underlying adaptive features. Polyploidy can regulate gene expression via chromatin opening, reawakening ancient evolutionary programs embryonality. Chromatin opening switches genes with bivalent domains that promote rapid induction response to signals or morphogenesis. Therefore, stress-associated polyploidy activate Myc proto-oncogenes, which further opening. Moreover, proto-oncogenes trigger polyploidization de novo accelerate genome accumulation already polyploid cells. As a result these cooperative effects, increase ability search for states cellular through regulatory network rewiring. This manifested epigenetic associated traits stemness, unicellularity, flexible energy metabolism, complex system DNA damage protection, combining primitive error-prone unicellular repair pathways, advanced error-free multicellular damage-buffering ability. These three features be considered important components increased adaptability evidence presented here contribute understanding resistance ploidy may useful development new methods prevention treatment oncological diseases.

Language: Английский

Citations

26
Biochemical Pathways of Cellular Mechanosensing/Mechanotransduction and Their Role in Neurodegenerative Diseases Pathogenesis DOI Creative Commons
Ilaria Tortorella, Chiara Argentati, Carla Emiliani

et al.

Cells, Journal Year: 2022, Volume and Issue: 11(19), P. 3093 - 3093

Published: Oct. 1, 2022

In this review, we shed light on recent advances regarding the characterization of biochemical pathways cellular mechanosensing and mechanotransduction with particular attention to their role in neurodegenerative disease pathogenesis. While mechanistic components these are mostly uncovered today, crosstalk between mechanical forces soluble intracellular signaling is still not fully elucidated. Here, recapitulate general concepts mechanobiology mechanisms that govern processes, examine stimuli response, highlighting effect organelles' homeostasis dysfunction. particular, discuss current knowledge about translation mechanosignaling into signaling, focusing those diseases encompass metabolic accumulation mutant proteins have as primary characteristics formation pathological aggregates, such Alzheimer's Disease, Huntington's Amyotrophic Lateral Sclerosis Parkinson's Disease. Overall, findings elucidate how may be crucial understand pathogenic underlying emphasize importance for identifying potential therapeutic targets.

Language: Английский

Citations

25
Neuronal DNA repair reveals strategies to influence CRISPR editing outcomes DOI Creative Commons
Gokul N. Ramadoss,

Samali J Namaganda,

Jennifer Hamilton

et al.

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

Published: June 26, 2024

Genome editing is poised to revolutionize treatment of genetic diseases, but poor understanding and control DNA repair outcomes hinders its therapeutic potential. especially understudied in nondividing cells like neurons, which must withstand decades damage without replicating. This lack knowledge limits the efficiency precision genome clinically relevant cells. To address this, we used induced pluripotent stem (iPSCs) iPSC-derived neurons examine how postmitotic human Cas9-induced damage. We discovered that can take weeks fully resolve this damage, compared just days isogenic iPSCs. Furthermore, Cas9-treated upregulated unexpected genes, including factors canonically associated with replication. Manipulating response chemical or perturbations allowed us direct neuronal toward desired outcomes. By studying cells, uncovered unforeseen challenges opportunities for precise editing.

Language: Английский

Citations

5
Integrating the Study of Polyploidy Across Organisms, Tissues, and Disease DOI
John P. Morris, Timour Baslan, Pamela S. Soltis

et al.

Annual Review of Genetics, Journal Year: 2024, Volume and Issue: 58(1), P. 297 - 318

Published: Sept. 4, 2024

Polyploidy is a cellular state containing more than two complete chromosome sets. It has largely been studied as discrete phenomenon in either organismal, tissue, or disease contexts. Increasingly, however, investigation of polyploidy across disciplines coalescing around common principles. For example, the recent Across Tree Life meeting considered contribution both organismal evolution over millions years and tumorigenesis much shorter timescales. Here, we build on this newfound integration with unified discussion organisms, cells, disease. We highlight how at multiple biological scales, thus eliminating outdated mindset its specialization. Additionally, discuss rules that are likely to all instances polyploidy. With increasing appreciation pervasive nature displays fascinating commonalities diverse contexts, inquiry related important topic rapidly becoming unified.

Language: Английский

Citations

5
Conserved chamber-specific polyploidy maintains heart function in Drosophila DOI Open Access
Archan Chakraborty, Nora G. Peterson, Juliet S. King

et al.

Development, Journal Year: 2023, Volume and Issue: 150(16)

Published: Aug. 1, 2023

Developmentally programmed polyploidy (whole-genome duplication) of cardiomyocytes is common across evolution. Functions such are essentially unknown. Here, in both Drosophila larvae and human organ donors, we reveal distinct levels cardiac chambers. In Drosophila, differential growth cell cycle signal sensitivity leads the heart chamber to reach a higher ploidy/cell size relative aorta chamber. Cardiac ploidy-reduced animals exhibit reduced size, stroke volume output, acceleration circulating hemocytes. These phenotypes mimic cardiomyopathies. Our results identify productive likely conserved roles for chambers suggest that precise ploidy sculpt many developing tissues. findings cardiomyocyte impact efforts block developmental improve injury recovery.

Language: Английский

Citations

12
Uncovering Cell Cycle Dysregulations and Associated Mechanisms in Cancer and Neurodegenerative Disorders: A Glimpse of Hope for Repurposed Drugs DOI
Dia Advani, Pravir Kumar

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: March 26, 2024

Language: Английский

Citations

4