Endogenous epitope tagging of eEF1A2 in mice reveals early embryonic expression of eEF1A2 and subcellular compartmentalisation of neuronal eEF1A1 and eEF1A2 DOI Creative Commons
Faith C.J. Davies, Grant F. Marshall,

Eleanor Pegram

и другие.

Molecular and Cellular Neuroscience, Год журнала: 2023, Номер 126, С. 103879 - 103879

Опубликована: Июль 8, 2023

All vertebrate species express two independently-encoded forms of translation elongation factor eEF1A. In humans and mice eEF1A1 eEF1A2 are 92 % identical at the amino acid level, but well conserved developmental switch between variants in specific tissues suggests existence important functional differences. Heterozygous mutations result neurodevelopmental disorders humans; mechanism pathogenicity is unclear, one hypothesis that there a dominant negative effect on during development. The high degree similarity eEF1A proteins has complicated expression analysis past; here we describe gene edited mouse line which have introduced V5 tag encoding eEF1A2. Expression using anti-V5 anti-eEF1A1 antibodies demonstrates that, contrast to prevailing view only expressed postnatally, it from as early E11.5 developing neural tube. Two colour immunofluorescence also reveals coordinated switching different regions postnatal brain. Completely reciprocal seen post-weaning brain with oligodendrocytes astrocytes neuronal soma. Although absent cell bodies after development, widely axons. This does not appear coincide myelin sheaths originating rather results localised within axon, suggesting both transcribed neurons show completely distinct subcellular localisation protein level. These findings will form an underlying framework for understanding how missense disorders.

Язык: Английский

RNA modifications in physiology and disease: towards clinical applications DOI Open Access
Sylvain Delaunay, Mark Helm, Michaela Frye

и другие.

Nature Reviews Genetics, Год журнала: 2023, Номер 25(2), С. 104 - 122

Опубликована: Сен. 15, 2023

Язык: Английский

Процитировано

141
Spatially resolved single-cell translatomics at molecular resolution DOI
Hu Zeng, Jiahao Huang, Jingyi Ren

и другие.

Science, Год журнала: 2023, Номер 380(6652)

Опубликована: Июнь 29, 2023

The precise control of messenger RNA (mRNA) translation is a crucial step in posttranscriptional gene regulation cellular physiology. However, it remains challenge to systematically study mRNA at the transcriptomic scale with spatial and single-cell resolution. Here, we report development ribosome-bound mapping (RIBOmap), highly multiplexed three-dimensional situ profiling method detect translatome. RIBOmap 981 genes HeLa cells revealed cell cycle-dependent translational colocalized functional modules. We mapped 5413 mouse brain tissues, yielding spatially resolved translatomic profiles for 119,173 revealing type-specific region-specific regulation, including remodeling during oligodendrocyte maturation. Our detected widespread patterns localized neuronal glial intact tissue networks.

Язык: Английский

Процитировано

106
De-centralizing the Central Dogma: mRNA translation in space and time DOI Creative Commons
Ashley M. Bourke, Andre Schwarz, Erin M. Schuman

и другие.

Molecular Cell, Год журнала: 2023, Номер 83(3), С. 452 - 468

Опубликована: Янв. 19, 2023

As our understanding of the cell interior has grown, we have come to appreciate that most cellular operations are localized, is, they occur at discrete and identifiable locations or domains. These domains contain enzymes, machines, other components necessary carry out regulate these localized operations. Here, review features one such operation: localization translation mRNAs within subcellular compartments observed across types organisms. We describe conceptual advantages "ingredients" mechanisms local translation. focus on nature mRNAs, how travel get this process is regulated. also evaluate current protein synthesis machines (ribosomes) their cadre regulatory elements, factors.

Язык: Английский

Процитировано

56
Understanding the cell: Future views of structural biology DOI Creative Commons
Martin Beck, Roberto Covino, Inga Hänelt

и другие.

Cell, Год журнала: 2024, Номер 187(3), С. 545 - 562

Опубликована: Фев. 1, 2024

Determining the structure and mechanisms of all individual functional modules cells at high molecular detail has often been seen as equal to understanding how work. Recent technical advances have led a flush high-resolution structures various macromolecular machines, but despite this wealth detailed information, our cellular function remains incomplete. Here, we discuss present-day limitations structural biology highlight novel technologies that may enable us analyze functions directly inside cells. We predict progression toward cell will involve shift conceptualizing 4D virtual reality using digital twins. These capture segments in highly enriched detail, include dynamic changes, facilitate simulations processes, leading experimentally testable predictions. Transferring biological questions into algorithms learn from existing data explore solutions ultimately unveil

Язык: Английский

Процитировано

22
Protein lifetimes in aged brains reveal a proteostatic adaptation linking physiological aging to neurodegeneration DOI Creative Commons
Verena Kluever, Belisa Russo, Sunit Mandad

и другие.

Science Advances, Год журнала: 2022, Номер 8(20)

Опубликована: Май 20, 2022

Aging is a prominent risk factor for neurodegenerative disorders (NDDs); however, the molecular mechanisms rendering aged brain particularly susceptible to neurodegeneration remain unclear. Here, we aim determine link between physiological aging and NDDs by exploring protein turnover using metabolic labeling quantitative pulse-SILAC proteomics. By comparing lifetimes physiologically young adult mice, found that in brains are increased ~20% affects distinct pathways linked NDDs. Specifically, set of neuroprotective proteins longer-lived brains, while some mitochondrial shorter-lived. Strikingly, observed previously unknown alteration proteostasis correlates parsimonious with high biosynthetic costs, revealing an overall adaptation preludes neurodegeneration. Our findings suggest future therapeutic paradigms, aimed at addressing these adaptations, might be able delay NDD onset.

Язык: Английский

Процитировано

44
The Role of PGC-1α-Mediated Mitochondrial Biogenesis in Neurons DOI
Mengjie Chen,

Ru-Yu Yan,

Jian-Sheng Luo

и другие.

Neurochemical Research, Год журнала: 2023, Номер 48(9), С. 2595 - 2606

Опубликована: Апрель 25, 2023

Язык: Английский

Процитировано

30
Subcytoplasmic location of translation controls protein output DOI Creative Commons

Ellen L. Horste,

Mervin M. Fansler, Ting Cai

и другие.

Molecular Cell, Год журнала: 2023, Номер 83(24), С. 4509 - 4523.e11

Опубликована: Дек. 1, 2023

The cytoplasm is highly compartmentalized, but the extent and consequences of subcytoplasmic mRNA localization in non-polarized cells are largely unknown. We determined enrichment TIS granules (TGs) rough endoplasmic reticulum (ER) through particle sorting isolated cytosolic mRNAs by digitonin extraction. When focusing on genes that encode non-membrane proteins, we observed 52% have transcripts enriched specific compartments. Compartment correlates with a combinatorial code based length, exon 3′ UTR-bound RNA-binding proteins. Compartment-biased differ functional classes their encoded proteins: TG-enriched low-abundance proteins strong transcription factors, whereas ER-enriched large expressed an important determinant protein abundance, which supported reporter experiments showing redirecting to ER increases expression. In summary, functionally compartmentalized local translation environments.

Язык: Английский

Процитировано

30
tRNA Dysregulation in Neurodevelopmental and Neurodegenerative Diseases DOI Creative Commons
Robert W. Burgess, Erik Storkebaum

Annual Review of Cell and Developmental Biology, Год журнала: 2023, Номер 39(1), С. 223 - 252

Опубликована: Июнь 20, 2023

Transfer RNAs (tRNAs) decode messenger RNA codons to peptides at the ribosome. The nuclear genome contains many tRNA genes for each amino acid and even anticodon. Recent evidence indicates that expression of these tRNAs in neurons is regulated, they are not functionally redundant. When specific nonfunctional, this results an imbalance between codon demand availability. Furthermore, spliced, processed, posttranscriptionally modified. Defects processes lead neurological disorders. Finally, mutations aminoacyl synthetases (aaRSs) also disease. Recessive several aaRSs cause syndromic disorders, while dominant a subset peripheral neuropathy, again due supply demand. While it clear disrupting biology often leads disease, additional research needed understand sensitivity changes.

Язык: Английский

Процитировано

29
VAP spatially stabilizes dendritic mitochondria to locally support synaptic plasticity DOI Creative Commons
Ojasee Bapat,

Tejas Purimetla,

Sarah Kruessel

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 4, 2024

Abstract Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses energy consumption hotspots susceptible to dysfunction when their supplies perturbed. Mitochondria stabilized near via the cytoskeleton provide local required for synaptic plasticity. However, mechanisms that tether stabilize mitochondria support unknown. We identified proteins exclusively tethering actin postsynaptic spines. find VAP, vesicle-associated membrane protein-associated protein implicated in amyotrophic lateral sclerosis, stabilizes To test if VAP-dependent stable mitochondrial compartments can locally plasticity, we used two-photon glutamate uncaging spine induction investigated induced adjacent uninduced VAP functions as a spatial stabilizer up ~60 min ruler determining ~30 μm dendritic segment supported during

Язык: Английский

Процитировано

16
Neuronal activity rapidly reprograms dendritic translation via eIF4G2:uORF binding DOI Creative Commons
Ezgi Hacisuleyman, Caryn Hale,

Natalie Noble

и другие.

Nature Neuroscience, Год журнала: 2024, Номер 27(5), С. 822 - 835

Опубликована: Апрель 8, 2024

Abstract Learning and memory require activity-induced changes in dendritic translation, but which mRNAs are involved how they regulated unclear. In this study, to monitor depolarization impacts local biology, we employed a dendritically targeted proximity labeling approach followed by crosslinking immunoprecipitation, ribosome profiling mass spectrometry. Depolarization of primary cortical neurons with KCl or the glutamate agonist DHPG caused rapid reprogramming protein expression, where proteins weakly correlated. For subset pre-localized messages, increased translation upstream open reading frames (uORFs) their downstream coding sequences, enabling localized production long-term potentiation, cell signaling energy metabolism. This activity-dependent was accompanied phosphorylation recruitment non-canonical initiation factor eIF4G2, translated uORFs were sufficient confer depolarization-induced, eIF4G2-dependent translational control. These studies uncovered an unanticipated mechanism uORF control eIF4G2 couples activity remodeling.

Язык: Английский

Процитировано

16