mRNAs, proteins and the emerging principles of gene expression control

Nature Reviews Genetics, Год журнала: 2020, Номер 21(10), С. 630 - 644

Опубликована: Июль 24, 2020

Язык: Английский

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Local translation in neurons: visualization and function

Nature Structural & Molecular Biology, Год журнала: 2019, Номер 26(7), С. 557 - 566

Опубликована: Июль 1, 2019

Язык: Английский

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Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments

Science, Год журнала: 2019, Номер 364(6441)

Опубликована: Май 16, 2019

Local translation in presynaptic terminals Proteins carry out most of the functions cells, including neurons, which are one morphologically complex cell types body. This poses challenges for how proteins can be supplied to remote regions where connections (synapses) made with other neurons. One solution neuron protein-supply problem involves local synthesis from messenger RNA (mRNA) molecules located at or near synapses. Hafner et al. used sequencing methods and superresolution microscopy show that axon contain hundreds mRNA as well machinery needed protein synthesis. Furthermore, were able use these components make participate synaptic transmission. Science , this issue p. eaau3644

Язык: Английский

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Spatially Stable Mitochondrial Compartments Fuel Local Translation during Plasticity

Cell, Год журнала: 2019, Номер 176(1-2), С. 73 - 84.e15

Опубликована: Янв. 1, 2019

Язык: Английский

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Precisely measured protein lifetimes in the mouse brain reveal differences across tissues and subcellular fractions

Nature Communications, Год журнала: 2018, Номер 9(1)

Опубликована: Окт. 8, 2018

The turnover of brain proteins is critical for organism survival, and its perturbations are linked to pathology. Nevertheless, protein lifetimes have been difficult obtain in vivo. They readily measured vitro by feeding cells with isotopically labeled amino acids, followed mass spectrometry analyses. In vivo generated from at least two sources: acids the diet, non-labeled degradation pre-existing proteins. This renders measurements difficult. Here we solved this problem rigorously a workflow that combines mouse isotopic labeling, spectrometry, mathematical modeling. We also established several independent approaches test validate results. enabled us measure accurate ~3500 high precision our data provided large set biologically significant observations, including pathway-, organelle-, organ-, or cell-specific effects, along comprehensive catalog extremely long-lived (ELLPs).

Язык: Английский

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Neuronal ribosomes exhibit dynamic and context-dependent exchange of ribosomal proteins

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Окт. 21, 2021

Abstract Owing to their morphological complexity and dense network connections, neurons modify proteomes locally, using mRNAs ribosomes present in the neuropil (tissue enriched for dendrites axons). Although ribosome biogenesis largely takes place nucleus perinuclear region, neuronal ribosomal protein (RP) have been frequently detected remotely, axons. Here, imaging profiling, we directly RP translation neuropil. Combining brief metabolic labeling with mass spectrometry, found that a group of RPs rapidly associated translating cytoplasm this incorporation was independent canonical biogenesis. Moreover, probability some regulated by location (neurites vs. cell bodies) changes cellular environment (following oxidative stress). Our results suggest new mechanisms local activation, repair and/or specialization translational machinery within processes, potentially allowing synapses rapid means regulate synthesis.

Язык: Английский

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Representational drift: Emerging theories for continual learning and experimental future directions

Current Opinion in Neurobiology, Год журнала: 2022, Номер 76, С. 102609 - 102609

Опубликована: Авг. 5, 2022

Язык: Английский

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Synaptic memory and CaMKII

Physiological Reviews, Год журнала: 2023, Номер 103(4), С. 2897 - 2945

Опубликована: Июнь 8, 2023

Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and long-term potentiation (LTP) were discovered within a decade of each other have been inextricably intertwined ever since. However, like many marriages, it has had its up downs. Based on the unique biochemical properties CaMKII, was proposed as memory molecule before any physiological linkage made to LTP. reviewed here, convincing CaMKII synaptic physiology behavior took decades. New technologies critical in this journey, including vitro brain slices, mouse genetics, single-cell molecular pharmacological reagents, structure, two-photon microscopy, new investigators attracted by exciting challenge. This review tracks journey assesses state marriage 40 years on. The collective literature impels us propose relatively simple model for involving following steps that drive process: 1) entry through N-methyl-d-aspartate (NMDA) receptors activates CaMKII. 2) undergoes autophosphorylation resulting constitutive, -independent activity exposure binding site NMDA receptor subunit GluN2B. 3) Active translocates postsynaptic density (PSD) binds cytoplasmic C-tail 4) CaMKII-GluN2B complex initiates structural rearrangement PSD may involve liquid-liquid phase separation. 5) involves PSD-95 scaffolding protein, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPARs), their transmembrane AMPAR-regulatory (TARP) auxiliary subunits, an accumulation AMPARs underlies potentiation. 6) stability modified is maintained complex. 7) By process exchange or interholoenzyme phosphorylation maintains face turnover. There are important proteins participate enlargement spine modulation maintain In we critically discuss data underlying steps. As will become clear, some these more firmly grounded than others, provide suggestions how evidence supporting can be strengthened or, based data, replaced. Although long one, prospect having detailed cellular understanding learning at hand.

Язык: Английский

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Analysis and prediction of protein stability based on interaction network, gene ontology, and KEGG pathway enrichment scores

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Год журнала: 2023, Номер 1871(3), С. 140889 - 140889

Опубликована: Янв. 5, 2023

Язык: Английский

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Loss of TDP‐43 oligomerization or RNA binding elicits distinct aggregation patterns

The EMBO Journal, Год журнала: 2023, Номер 42(17)

Опубликована: Июль 11, 2023

Abstract Aggregation of the RNA‐binding protein TAR DNA‐binding 43 (TDP‐43) is key neuropathological feature neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). In physiological conditions, TDP‐43 predominantly nuclear, forms oligomers, contained in biomolecular condensates assembled by liquid–liquid phase separation (LLPS). disease, cytoplasmic or intranuclear inclusions. How transitions from to pathological states remains poorly understood. Using a variety cellular systems express structure‐based variants, human neurons cell lines with near‐physiological expression levels, we show that oligomerization RNA binding govern stability, splicing functionality, LLPS, subcellular localization. Importantly, our data reveal modulated binding. By mimicking impaired proteasomal activity observed ALS/FTLD patients, found monomeric inclusions cytoplasm, whereas its binding‐deficient counterpart aggregated nucleus. These differentially localized aggregates emerged via distinct pathways: LLPS‐driven aggregation nucleus aggresome‐dependent inclusion formation cytoplasm. Therefore, work unravels origins heterogeneous species reminiscent those occurring proteinopathy patients.

Язык: Английский

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