A comprehensive atlas of the aging vertebrate brain reveals signatures of progressive proteostasis dysfunction DOI Creative Commons
Domenico Di Fraia, Antonio Marino, Jae Ho Lee

et al.

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

Published: July 24, 2023

Aging and neurodegeneration entail diverse cellular molecular hallmarks. Here, we studied the effects of aging on transcriptome, translatome, multiple layers proteome in brain a short-lived killifish. We reveal that causes widespread reduction proteins enriched basic amino acids is independent mRNA regulation, it not due to impaired proteasome activity. Instead, identify cascade events where aberrant translation pausing leads reduced ribosome availability resulting remodeling independently transcriptional regulation. Our research uncovers vulnerable point brain's biology - biogenesis DNA/RNA binding proteins. This vulnerability may represent unifying principle connects various hallmarks, encompassing genome integrity biosynthesis macromolecules.

Language: Английский

FUS ALS neurons activate major stress pathways and reduce translation as an early protective mechanism against neurodegeneration DOI Creative Commons
Barbara Szewczyk, René Günther,

Julia Japtok

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(2), P. 112025 - 112025

Published: Jan. 25, 2023

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder causing progressive loss of motor neurons. Mutations in Fused sarcoma (FUS) leading to its cytoplasmic mislocalization cause subset ALS. Under stress, mutant FUS localizes stress granules (SGs)-cytoplasmic condensates composed RNA and various proteins. Aberrant dynamics SGs linked the pathology Here, using neurons (MNs) derived from human induced pluripotent stem cells, we show that, FUS, MN disturbed. Additionally, heat-shock response (HSR) integrated (ISR) involved regulation are upregulated MNs. HSR activation correlates with amount mislocalization. While inhibition SG formation, translation, or ISR does not influence survival ALS neurons, proteotoxicity that cannot be compensated pathways main driver neurodegeneration early

Language: Английский

Citations

42
Amyloid Precursor Protein and Alzheimer’s Disease DOI Open Access

Kseniia S. Orobets,

Andrey L. Karamyshev

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(19), P. 14794 - 14794

Published: Sept. 30, 2023

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders associated with age or inherited mutations. It characterized by severe dementia in late stages that affect memory, cognitive functions, and daily life overall. AD progression linked to accumulation cytotoxic amyloid beta (Aβ) hyperphosphorylated tau protein combined other pathological features such as synaptic loss, defective energy metabolism, imbalances protein, metal homeostasis. Several treatment options for are under investigation, including antibody-based therapy stem cell transplantation. Amyloid precursor (APP) a membrane considered play main role pathology. known APP physiological conditions follows non-amyloidogenic pathway; however, it can proceed an amyloidogenic scenario, which leads generation extracellular deleterious Aβ plaques. Not all steps biogenesis clear so far, these questions should be addressed future studies. complex chronic many factors contribute progression.

Language: Английский

Citations

35
Reverse electron transfer is activated during aging and contributes to aging and age‐related disease DOI
Suman Rimal,

Ishaq Tantray,

Yu Li

et al.

EMBO Reports, Journal Year: 2023, Volume and Issue: 24(4)

Published: Feb. 16, 2023

Language: Английский

Citations

26
Proteostasis disruption and senescence in Alzheimer’s disease pathways to neurodegeneration DOI
Riya Thapa, Asif Ahmad Bhat, Moyad Shahwan

et al.

Brain Research, Journal Year: 2024, Volume and Issue: 1845, P. 149202 - 149202

Published: Aug. 30, 2024

Language: Английский

Citations

9
The Role of mRNA Quality Control in the Aging of Caenorhabditis elegans DOI Open Access
H.C Kwon, Yunkyu Bae, Seung‐Jae Lee

et al.

Molecules and Cells, Journal Year: 2023, Volume and Issue: 46(11), P. 664 - 671

Published: Nov. 1, 2023

The proper maintenance of mRNA quality that is regulated by diverse surveillance pathways essential for cellular homeostasis and highly conserved among eukaryotes.Here, we review findings regarding the role control in aging longevity Caenorhabditis elegans, an outstanding model research.We discuss recently discovered functions regulation nonsense-mediated decay, ribosome-associated control, splicing C. elegans.We describe how contributes to conferred various regimens, including inhibition insulin/insulin-like growth factor 1 (IGF-1) signaling, dietary restriction, reduced mechanistic target rapamycin signaling.This provides valuable information relationship between which may lead insights into healthy complex organisms, humans.

Language: Английский

Citations

21
Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats DOI Creative Commons
Yi‐Ju Tseng,

Amy Krans,

Indranil Malik

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(10), P. 5928 - 5949

Published: Feb. 27, 2024

A GGGGCC (G4C2) hexanucleotide repeat expansion in C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), while a CGG trinucleotide FMR1 leads to the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). These GC-rich repeats form RNA secondary structures that support repeat-associated non-AUG (RAN) translation of toxic proteins contribute disease pathogenesis. Here we assessed whether these same might trigger stalling interfere with translational elongation. We find depletion ribosome-associated quality control (RQC) factors NEMF, LTN1 ANKZF1 markedly boost RAN product accumulation from both G4C2 overexpression reduces production reporter assays C9ALS/FTD patient iPSC-derived neurons. also detected partially made products whose abundance increased RQC factor depletion. Repeat sequence, rather than amino acid content, is central impact on translation-suggesting role for structure processes. Together, findings suggest ribosomal pathway activation during inhibits generation products. propose augmenting activity as therapeutic strategy disorders.

Language: Английский

Citations

7
NEMF-mediated Listerin-independent mitochondrial translational surveillance by E3 ligase Pirh2 and mitochondrial protease ClpXP DOI Creative Commons
Liang Lv,

Jinyou Mo,

Yumin Qing

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(3), P. 113860 - 113860

Published: Feb. 26, 2024

The ribosome-associated protein quality control (RQC) pathway acts as a translational surveillance mechanism to maintain proteostasis. In mammalian cells, the cytoplasmic RQC involves nuclear export mediator factor (NEMF)-dependent recruitment of E3 ligase Listerin ubiquitinate ribosome-stalled nascent polypeptides on lysine residue for degradation. However, nuclear-encoded mitochondrial remains elusive, these peptides can be partially imported into mitochondria through translocons, restricting accessibility by Listerin. Here, we identify Listerin-independent organelle-specific that NEMF-mediated carboxy-terminal poly-alanine modification. pathway, proteins carrying C-end poly-Ala tails are recognized cytosolic Pirh2 and ClpXP protease in mitochondria, which coordinately clear polypeptides. Defects this elimination result aggregates integrity failure, thus providing potential molecular mitochondrial-associated human diseases.

Language: Английский

Citations

6
Translational regulation by ribosome-associated quality control in neurodegenerative disease, cancer, and viral infection DOI Creative Commons
Bingwei Lu

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: Sept. 14, 2022

Translational control at the initiation, elongation, and termination steps exerts immediate effects on rate as well spatiotemporal dynamics of new protein synthesis, shaping composition proteome. is particularly important for cells under stress during viral infection or in disease conditions such cancer neurodegenerative diseases. Much has been learned about mechanisms acting translational initiation step normal pathological conditions. However, problems elongation translation can lead to ribosome stalling collision, which will trigger ribosome-associated quality (RQC) mechanism. Inadequate RQC may accumulation faulty products that perturb homeostasis (proteostasis). Proteostasis signifies a cellular state folding, degradation proteins are maintained homeostatic an intact proteome preserved. Cellular capacity preserve proteostasis declines with age, thought contribute age-related failure manifested formation aberrant aggregates, epitomized by amyloid plaques Alzheimer’s (AD), defining feature The root cause aggregation still enigmatic. Here I review recent studies supporting resulting from inadequate collision problematic mRNAs be represent novel therapeutic targets also evidence regulation operative infection. Better understanding mechanism strategies against diseases, cancer, infections, including ongoing COVID-19 pandemic.

Language: Английский

Citations

20
Molecular Highway Patrol for Ribosome Collisions DOI Creative Commons
Kaushik Viswanathan Iyer, Max Müller, Lena Sophie Tittel

et al.

ChemBioChem, Journal Year: 2023, Volume and Issue: 24(20)

Published: June 29, 2023

During translation, messenger RNAs (mRNAs) are decoded by ribosomes which can stall for various reasons. These include chemical damage, codon composition, starvation, or translation inhibition. Trailing collide with stalled ribosomes, potentially leading to dysfunctional toxic proteins. Such aberrant proteins form aggregates and favor diseases, especially neurodegeneration. To prevent this, both eukaryotes bacteria have evolved different pathways remove faulty nascent peptides, mRNAs defective from the collided complex. In eukaryotes, ubiquitin ligases play central roles in triggering downstream responses several complexes been characterized that split affected facilitate degradation of components. As signal stress cells, additional response triggered when collisions sensed. inhibit modulate cell survival immune responses. Here, we summarize current state knowledge about rescue ribosome collisions.

Language: Английский

Citations

11
Alzheimer’s disease may develop from changes in the immune system, cell cycle, and protein processing following alterations in ribosome function DOI Creative Commons
Akiko Yamakawa,

Mutsumi Suganuma,

Risa Mitsumori

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 30, 2025

The prevalence of Alzheimer's disease (AD) is increasing as society ages. details AD pathogenesis have not been fully elucidated, and a comprehensive gene expression analysis the process leading up to onset would be helpful for understanding mechanism. We performed an RNA sequencing on cohort 1227 Japanese blood samples, representing 424 patients, 543 individuals with mild cognitive impairment (MCI), 260 cognitively normal (CN) individuals. A total 883 1169 statistically significant differentially expressed genes (DEGs) were identified between CN MCI (CN-MCI) (MCI-AD), respectively. Pathway analyses using these DEGs, followed by protein–protein interaction network analysis, revealed key roles ribosomal function in progression, whereas immune responses, cell cycle, protein processing endoplasmic reticulum involved progression. Our findings indicate that might associated changes system, following alterations during stage, although validation brain tissue samples will necessary future. Given known effectiveness delaying progression preventing AD, related emerge biomarkers early diagnosis.

Language: Английский

Citations

0