Proteostasis and Ribostasis Impairment as Common Cell Death Mechanisms in Neurodegenerative Diseases DOI Creative Commons
Su Min Lim, Minyeop Nahm, Seung Hyun Kim

et al.

Journal of Clinical Neurology, Journal Year: 2023, Volume and Issue: 19(2), P. 101 - 101

Published: Jan. 1, 2023

The cellular homeostasis of proteins (proteostasis) and RNA metabolism (ribostasis) are essential for maintaining both the structure function brain. However, aging, stress conditions, genetic contributions cause disturbances in proteostasis ribostasis that lead to protein misfolding, insoluble aggregate deposition, abnormal ribonucleoprotein granule dynamics. In addition neurons being primarily postmitotic, nondividing cells, they more susceptible persistent accumulation aggregates. Indeed, defects associated with failure maintain common pathogenic components age-related neurodegenerative diseases, including Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis. Furthermore, neuronal deposition misfolded aggregated can increased toxicity impaired physiological function, which dysfunction cell death. There is recent evidence irreversible liquid-liquid phase separation (LLPS) responsible formation disease-related proteins, tau, α-synuclein, RNA-binding transactive response DNA-binding 43, fused sarcoma, heterogeneous nuclear A1. Investigations LLPS its control therefore suggest chaperone/disaggregase, reverse aggregation, valuable therapeutic targets effective treatments neurological diseases. Here we review discuss studies highlight importance understanding death mechanisms

Language: Английский

RNA Dynamics in Alzheimer’s Disease DOI Creative Commons
Agnieszka Rybak‐Wolf, Mireya Plass

Molecules, Journal Year: 2021, Volume and Issue: 26(17), P. 5113 - 5113

Published: Aug. 24, 2021

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that heavily burdens healthcare systems worldwide. There a significant requirement to understand still unknown molecular mechanisms underlying AD. Current evidence shows two of major features AD are transcriptome dysregulation and altered function RNA binding proteins (RBPs), both which lead changes in expression different species, including microRNAs (miRNAs), circular RNAs (circRNAs), long non-coding (lncRNAs), messenger (mRNAs). In this review, we will conduct comprehensive overview how dynamics leads differential short species. We describe RBP impacts Furthermore, also show abundance specific species linked pathology

Language: Английский

Citations

46
RNA Modifications and RNA Metabolism in Neurological Disease Pathogenesis DOI Open Access

Biswanath Chatterjee,

Che‐Kun James Shen,

Pritha Majumder

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(21), P. 11870 - 11870

Published: Nov. 1, 2021

The intrinsic cellular heterogeneity and molecular complexity of the mammalian nervous system relies substantially on dynamic nature spatiotemporal patterning gene expression. These features expression are achieved in part through mechanisms involving various epigenetic processes such as DNA methylation, post-translational histone modifications, non-coding RNA activity, amongst others. In concert, another regulatory layer by which bases sugar residues chemically modified enhances neuronal transcriptome complexity. Similar modifications other systems collectively constitute epitranscriptome that integrates impacts physiological processes. is reshaped constantly to regulate vital development, differentiation stress responses. Perturbations can lead pathogenic conditions, including cancer, cardiovascular abnormalities neurological diseases. Recent advances next-generation sequencing technologies have enabled us identify locate bases/sugars different species. modulate stability, transport and, most importantly, translation RNA. this review, we discuss formation functions some frequently observed modifications—including methylations adenine cytosine bases, isomerization uridine pseudouridine—at layers metabolism, together with their contributions abnormal conditions neurodevelopmental disorders.

Language: Английский

Citations

45
Expression patterns of NKCC1 in neurons and non-neuronal cells during cortico-hippocampal development DOI Creative Commons
Samu Kurki, Pavel Uvarov, Alexey S. Pospelov

et al.

Cerebral Cortex, Journal Year: 2022, Volume and Issue: 33(10), P. 5906 - 5923

Published: Dec. 27, 2022

Abstract The Na-K-2Cl cotransporter NKCC1 is widely expressed in cells within and outside the brain. However, our understanding of its roles brain functions throughout development, as well neuropsychiatric neurological disorders, has been severely hindered by lack reliable data on developmental (sub)cellular expression patterns. We provide here first properly controlled analysis protein various cell types mouse using custom-made antibodies an knock-out validated immunohistochemical procedure, with parallel based advanced mRNA approaches. are at remarkably high levels oligodendrocytes. In immature neurons, was located somata, whereas adult only could be clearly detected. immunoreactivity also seen microglia, astrocytes, developing pericytes, progenitor dentate gyrus. Finally, a differential splice variants observed, NKCC1a predominating non-neuronal NKCC1b neurons. Taken together, cellular basis for enable identification major limitations promises development neuron-targeting NKCC1-blockers.

Language: Английский

Citations

33
Simultaneous CRISPR screening and spatial transcriptomics reveals intracellular, intercellular, and functional transcriptional circuits DOI Creative Commons
Loïc Binan,

Serwah Danquah,

Vera Valakh

et al.

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

Published: Dec. 1, 2023

Pooled optical screens have enabled the study of cellular interactions, morphology, or dynamics at massive scale, but not yet leveraged power highly-plexed single-cell resolved transcriptomic readouts to inform molecular pathways. Here, we present Perturb-FISH, which bridges these approaches by combining imaging spatial transcriptomics with parallel detection in situ amplified guide RNAs. We show that Perturb-FISH recovers intracellular effects are consistent Perturb-seq results a screen lipopolysaccharide response cultured monocytes, and uncover new intercellular density-dependent regulation innate immune response. further pair functional readout autism spectrum disorder risk genes, showing common calcium activity phenotypes induced pluripotent stem cell derived astrocytes their associated genetic interactions dysregulated is thus generally applicable method for studying associations biology resolution.

Language: Английский

Citations

18
Ribosome inactivation regulates translation elongation in neurons DOI Creative Commons
Bastian Popper,

Martina Bürkle,

Giuliana Ciccopiedi

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(2), P. 105648 - 105648

Published: Jan. 15, 2024

Cellular plasticity is crucial for adapting to ever-changing stimuli. As a result, cells consistently reshape their translatome, and, consequently, proteome. The control of translational activity has been thoroughly examined at the stage translation initiation. However, regulation ribosome speed in widely unknown. In this study, we utilized timed runoff approach along with proteomics and transmission electron microscopy, investigate global kinetics cells. We found that speeds vary amongst various cell types, such as astrocytes, induced pluripotent human stem cells, neural rat neurons. Of all types studied, mature cortical neurons exhibit highest rate translation. This finding particularly remarkable because express eEF2 lower levels than other types. Neurons solve conundrum by inactivating fraction ribosomes. increase leads reduction inactive ribosomes an enhancement active ones. Processes alter demand ribosomes, like neuronal excitation, cause increased inactivation redundant eEF2-dependent manner.Our data suggest novel regulatory mechanism which dynamically inactivate facilitate remodelling. These findings have important implications developmental brain disorders characterised by, among things, aberrant

Language: Английский

Citations

8
RNA supply drives physiological granule assembly in neurons DOI Creative Commons

Karl E. Bauer,

Niklas Bargenda, Rico Schieweck

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: May 19, 2022

Membraneless cytoplasmic condensates of mRNAs and proteins, known as RNA granules, play pivotal roles in the regulation mRNA fate. Their maintenance fine-tunes time location protein expression, affecting many cellular processes, which require complex distribution. Here, we report that granules-monitored by DEAD-Box helicase 6 (DDX6)-disassemble during neuronal maturation both cell culture vivo. This process requires function, synaptic inhibition results reversible granule assembly. Importantly, assembly is dependent on RNA-binding Staufen2, for its role localization. Altering levels free reveals availability facilitates DDX6 formation. Specifically depleting from granules confirms an important driver Moreover, required upon inhibition. Together, this data demonstrates how supply favors assembly, not only impacts subcellular localization but also translation-dependent plasticity, learning, memory.

Language: Английский

Citations

19
RNA binding proteins in senescence: A potential common linker for age-related diseases? DOI
Angelica Varesi, Lucrezia Irene Maria Campagnoli, Annalisa Barbieri

et al.

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 88, P. 101958 - 101958

Published: May 20, 2023

Language: Английский

Citations

12
RNA granules in flux: dynamics to balance physiology and pathology DOI
Michael Kiebler,

Karl E. Bauer

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 4, 2024

Language: Английский

Citations

3
Dilated cardiomyopathy-associated RNA Binding Motif Protein 20 regulates long pre-mRNAs in neurons DOI Open Access
Giulia Di Bartolomei,

Raul Ortiz,

Dietmar Schreiner

et al.

Published: Jan. 8, 2025

Precise coordination of molecular programs and neuronal growth govern the formation, maintenance, adaptation circuits. RNA metabolism has emerged as a key regulatory node neural development nervous system pathologies. To uncover cell-type-specific regulators, we systematically investigated expression recognition motif-containing proteins in mouse neocortex. Surprisingly, found RBM20, an alternative splicing regulator associated with dilated cardiomyopathy, to be expressed cortical parvalbumin interneurons mitral cells olfactory bulb. Genome-wide mapping RBM20 target mRNAs revealed that binds pre-mRNAs distal intronic regions. Loss only modest impact on splice isoforms but results significant reduction array mature cytoplasm. This phenotype is particularly pronounced for genes long introns encode synaptic proteins. We hypothesize ensures fidelity pre-mRNA by suppressing non-productive events genes. work highlights common requirement RBM20-dependent transcriptome regulation cardiomyocytes neurons demonstrates major genetic risk factor heart disease impacts gene expression.

Language: Английский

Citations

0
Dilated cardiomyopathy-associated RNA Binding Motif Protein 20 regulates long pre-mRNAs in neurons DOI Open Access
Giulia Di Bartolomei,

Raul Ortiz,

Dietmar Schreiner

et al.

Published: Jan. 8, 2025

Precise coordination of molecular programs and neuronal growth govern the formation, maintenance, adaptation circuits. RNA metabolism has emerged as a key regulatory node neural development nervous system pathologies. To uncover cell-type-specific regulators, we systematically investigated expression recognition motif-containing proteins in mouse neocortex. Surprisingly, found RBM20, an alternative splicing regulator associated with dilated cardiomyopathy, to be expressed cortical parvalbumin interneurons mitral cells olfactory bulb. Genome-wide mapping RBM20 target mRNAs revealed that binds pre-mRNAs distal intronic regions. Loss only modest impact on splice isoforms but results significant reduction array mature cytoplasm. This phenotype is particularly pronounced for genes long introns encode synaptic proteins. We hypothesize ensures fidelity pre-mRNA by suppressing non-productive events genes. work highlights common requirement RBM20-dependent transcriptome regulation cardiomyocytes neurons demonstrates major genetic risk factor heart disease impacts gene expression.

Language: Английский

Citations

0