Nuclear translocation of LINE-1 encoded ORF1p alters nuclear envelope integrity and disrupts nucleocytoplasmic transport in human neurons DOI Open Access

Rania Znaidi,

Olivia Massiani-Beaudoin,

Philippe Mailly

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 14, 2023

Abstract LINE-1 retrotransposons are emerging as possible culprits in neurodegenerative diseases. However, the molecular mechanisms underlying pathogenic role of and their encoded proteins ORF1p ORF2p still not completely understood. While endonuclease reverse transcriptase activities have been associated with DNA damage inflammation, no has yet assigned to ORF1p. Using a neuronal model oxidative stress displaying increased expression, we report here that stress-dependently translocated into nucleus, localized nuclear envelope directly interacted import proteins, pore complex components inner lamina. Stress-dependent targeting by altered integrity, disrupted nucleocytoplasmic transport induced heterochromatin destructuration, features diseases aging. Neurons post-mortem Parkinson disease (PD) patients non-PD affected controls expressed levels correlated shape PD. Overexpression neurons absence recapitulated dysfunctions loss circularity. Stress-induced alterations were restored blocking or small molecule remodelin. This study thus reveals retrotransposition- ORF2p- independent action at points novel target for neuroprotection.

Language: Английский

The role of cellular senescence in neurodegenerative diseases DOI Creative Commons
Yating Wang, Kamil Kuča, You Li

et al.

Archives of Toxicology, Journal Year: 2024, Volume and Issue: 98(8), P. 2393 - 2408

Published: May 15, 2024

Increasing evidence has revealed that cellular senescence drives NDs, including Alzheimer's disease (AD) and Parkinson's disease. Different senescent cell populations secrete senescence-associated secretory phenotypes (SASP), matrix metalloproteinase-3, interleukin (IL)-1α, IL-6, IL-8, which can harm adjacent microglia. Moreover, these cells possess high expression levels of hallmarks (p16 p21) elevated β-galactosidase activity in vitro vivo ND models. These contribute to the deposition β-amyloid tau-protein tangles. Selective clearance SASP regulation by inhibiting p38/mitogen-activated protein kinase nuclear factor kappa B signaling attenuate load prevent tangle deposition, thereby improving cognitive performance AD mouse In addition, telomere shortening, a biomarker, is associated with increased risks. Telomere dysfunction causes senescence, stimulating tumor necrosis factor-α, IL-1β secretions. The forced telomerase activators prevents yielding considerable neuroprotective effects. This review elucidates mechanism pathogenesis, suggesting strategies eliminate or restore normal phenotype for treating such diseases.

Language: Английский

Citations

20
High order expression dependencies finely resolve cryptic states and subtypes in single cell data DOI Creative Commons
Abel Jansma, Yuelin Yao, Jareth C. Wolfe

et al.

Molecular Systems Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Language: Английский

Citations

1
Canalizing cell fate by transcriptional repression DOI Creative Commons
Bryce Lim, Katrin Domsch, Moritz Mall

et al.

Molecular Systems Biology, Journal Year: 2024, Volume and Issue: 20(3), P. 144 - 161

Published: Feb. 1, 2024

Abstract Precision in the establishment and maintenance of cellular identities is crucial for development multicellular organisms requires tight regulation gene expression. While extensive research has focused on understanding cell type-specific activation, complex mechanisms underlying transcriptional repression alternative fates are not fully understood. Here, we provide an overview repressive involved fate regulation. We discuss molecular machinery responsible suppressing highlight role sequence-specific transcription factors (TFs) this process. Depletion these TFs can result unwanted expression increased plasticity. suggest that recruit complexes to their cis-regulatory elements, enabling them modulate chromatin accessibility a context-dependent manner. This modulation effectively suppresses master regulators programs downstream targets. The modularity dynamic behavior enables limited number repressors canalize maintain major minor decisions at different stages development.

Language: Английский

Citations

7
Zn(ii)-driven impact of monomeric transthyretin on amyloid-β amyloidogenesis DOI Creative Commons
Yelim Yi, Bokyung Kim, M.W Kim

et al.

Chemical Science, Journal Year: 2025, Volume and Issue: 16(10), P. 4366 - 4373

Published: Jan. 1, 2025

Zn( ii ) coordination to monomeric transthyretin (M-TTR) forms a ternary complex with amyloid-β (Aβ) peptides and promotes their hydrolysis, which directs M-TTR's anti-amyloidogenic activity through inhibiting primary nucleation.

Language: Английский

Citations

0
Ferroptosis in neurodegenerative diseases: mechanisms and therapeutic potential of stem cell derivatives DOI Creative Commons
Ting Zhang, Yun Zhang,

Jinpeng Xie

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: March 21, 2025

Ferroptosis, a non-apoptotic, iron-dependent form of regulated cell death, is closely related to the pathogenesis neurodegenerative diseases. Stem cells and their derivatives exhibit remarkable potential in modulating ferroptosis, offering promising therapeutic intervention for In this review, we systematically explore neurological aging its association with cognitive impairment diseases, focus on molecular mechanisms ferroptosis diseases strategies stem

Language: Английский

Citations

0
Imaging Probes for the Detection of Brain Microenvironment DOI
Shiming Zhang, Tianyu Wang,

Tianzi Gao

et al.

Colloids and Surfaces B Biointerfaces, Journal Year: 2025, Volume and Issue: unknown, P. 114677 - 114677

Published: April 1, 2025

Language: Английский

Citations

0
Zebrafish optic nerve injury results in systemic retinal ganglion cell dedifferentiation DOI Creative Commons

Akin Ali,

Hannah Schriever, Dennis Kostka

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

Abstract Retinal ganglion cells (RGCs) are the sole projection neurons connecting retina to brain and therefore play a critical role in vision. Death of RGCs during glaucoma, optic neuropathies after ocular trauma results irreversible loss vision as do not regenerate human eye. Moreover, there no FDA approved therapies that prevent RGC death and/or promote survival diseased or injured There is need better understand molecular underpinnings neuroprotection develop effective therapeutic approaches preserve damaged RGCs. Unlike mammals, zebrafish resilient nerve injury, even complete transection nerve. Here, we leveraged this unique model utilized single-cell RNA sequencing characterize responses injury identify putative neuroprotective regenerative pathways. heterogeneous studies mice have shown differential resiliency across subtypes. Our demonstrated all subtypes zebrafish. Quantifying changes gene expression revealed upregulation progenitor markers well distinct early late phases response. This shift causes injury-responsive resemble subtype 3, low frequency population endogenous immature normally maintained wild-type, uninjured adult retina. A similar but restricted transcriptomic response contralateral eye was also detected, highlighting systemic unilateral injury. Taken together, these demonstrate dedifferentiate may be novel mechanism mediating their cell capabilities. Author Summary connect essential for Their conditions like affecting over 70 million people worldwide, leads permanent blindness, with FDA-approved treatments it. In study, used next-generation technologies at level. We discovered survive damage by temporarily shifting into less mature state, resembling rare found animals. identified many genes whose RGCs, work significant because our detailed characterization identifies dedifferentiation an response, possibly important axon regrowth. The pathways potential targets enable

Language: Английский

Citations

0
Systematic transcriptomics analysis of calorie restriction and rapamycin unveils their synergistic interaction in prolonging cellular lifespan DOI Creative Commons
Yizhong Zhang,

Arshia Naaz,

Trishia Yi Ning Cheng

et al.

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: May 14, 2025

Aging is a multifaceted biological process marked by the decline in both mitotic and postmitotic cellular function, often central to development of age-related diseases. In pursuit slowing or even reversing aging process, prominent strategy significant interest calorie restriction (CR), also known as dietary restriction, potential influence drug called rapamycin (RM). Both CR RM have demonstrated capacity extend healthspan lifespan across diverse array species, including yeast, worms, flies, mice. Nevertheless, their individual combined effects on cells, well comparative analysis, remain areas that demand thorough investigation. this study, we employ RNA-sequencing methodologies comprehensively analyze impact CR, RM, combination (CR + RM) gene expression yeast cells. Our analysis uncovers distinctive, overlapping, contrasting patterns regulation, illuminating unique shared RM. Furthermore, transcriptional synergistic interaction validated extending human

Language: Английский

Citations

0
Nuclear translocation of the LINE-1 encoded ORF1 protein alters nuclear envelope integrity in human neurons DOI Creative Commons

Rania Znaidi,

Olivia Massiani-Beaudoin,

Philippe Mailly

et al.

Brain Research, Journal Year: 2025, Volume and Issue: unknown, P. 149579 - 149579

Published: March 1, 2025

LINE-1 retrotransposons are increasingly implicated in aging and neurodegenerative diseases, yet the precise pathogenic mechanisms remain elusive. While endonuclease reverse transcriptase activities of LINE-1-encoded ORF2p can induce DNA damage inflammation, a role ORF1p cellular dysfunctions stays unassigned. Here we demonstrate, using neuronal model, that translocates into nucleus upon arsenite-induced stress, directly interacting with nuclear import (KPNB1), pore complex (NUP153), lamina (Lamin B1) proteins. Nuclear translocation disrupts integrity, nucleocytoplasmic transport, heterochromatin structure, features linked to neurodegeneration aging. Elevated levels induced either by overexpression, or as observed Parkinson's disease post-mortem brain tissues correlate impaired envelope (NE) morphology. Stress-induced alterations mitigated blocking anti-aging drug remodelin. This study thus reveals action human neurons driving NE thereby contributing LINE-1-mediated cell toxicity.

Language: Английский

Citations

0
Lycopene attenuates D-galactose-induced memory and behavioral deficits by mediating microbiota-SCFAs-gut-brain axis balance in female CD-1 mice DOI
Jia Wang, Yuqi Shen, Lu Li

et al.

The Journal of Nutritional Biochemistry, Journal Year: 2024, Volume and Issue: unknown, P. 109777 - 109777

Published: Oct. 1, 2024

Language: Английский

Citations

2