The brain's dark transcriptome: Sequencing RNA in distal compartments of neurons and glia DOI Creative Commons
Seth A. Ament, Alexandros Poulopoulos

Current Opinion in Neurobiology, Journal Year: 2023, Volume and Issue: 81, P. 102725 - 102725

Published: May 15, 2023

Transcriptomic approaches are powerful strategies to map the molecular diversity of cells in brain. Single-cell genomic atlases have now been compiled for entire mammalian brains. However, complementary techniques only just beginning subcellular transcriptomes from distal cellular compartments. We review single-cell datasets alongside subtranscriptome data brain explore development and diversity. discuss how RNA-seq misses transcripts localized away cell bodies, which form 'dark transcriptome' brain: a collection subtranscriptomes dendrites, axons, growth cones, synapses, endfeet with important roles function. Recent advances transcriptome sequencing reveal these elusive pools RNA. outline success stories date uncovering constituent neurons glia, as well present emerging toolkit that is accelerating pace discovery.

Language: Английский

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

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 25(2), P. 104 - 122

Published: Sept. 15, 2023

Language: Английский

Citations

132
Spatially resolved single-cell translatomics at molecular resolution DOI
Hu Zeng, Jiahao Huang, Jingyi Ren

et al.

Science, Journal Year: 2023, Volume and Issue: 380(6652)

Published: June 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.

Language: Английский

Citations

105
De-centralizing the Central Dogma: mRNA translation in space and time DOI Creative Commons
Ashley M. Bourke, Andre Schwarz, Erin M. Schuman

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(3), P. 452 - 468

Published: Jan. 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.

Language: Английский

Citations

55
Understanding the cell: Future views of structural biology DOI Creative Commons
Martin Beck, Roberto Covino, Inga Hänelt

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(3), P. 545 - 562

Published: Feb. 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

Language: Английский

Citations

21
Protein lifetimes in aged brains reveal a proteostatic adaptation linking physiological aging to neurodegeneration DOI Creative Commons
Verena Kluever, Belisa Russo, Sunit Mandad

et al.

Science Advances, Journal Year: 2022, Volume and Issue: 8(20)

Published: May 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.

Language: Английский

Citations

44
Subcytoplasmic location of translation controls protein output DOI Creative Commons

Ellen L. Horste,

Mervin M. Fansler, Ting Cai

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(24), P. 4509 - 4523.e11

Published: Dec. 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.

Language: Английский

Citations

30
The Role of PGC-1α-Mediated Mitochondrial Biogenesis in Neurons DOI
Mengjie Chen,

Ru-Yu Yan,

Jian-Sheng Luo

et al.

Neurochemical Research, Journal Year: 2023, Volume and Issue: 48(9), P. 2595 - 2606

Published: April 25, 2023

Language: Английский

Citations

28
tRNA Dysregulation in Neurodevelopmental and Neurodegenerative Diseases DOI Creative Commons
Robert W. Burgess, Erik Storkebaum

Annual Review of Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 39(1), P. 223 - 252

Published: June 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.

Language: Английский

Citations

27
VAP spatially stabilizes dendritic mitochondria to locally support synaptic plasticity DOI Creative Commons
Ojasee Bapat,

Tejas Purimetla,

Sarah Kruessel

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 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

Language: Английский

Citations

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

Natalie Noble

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(5), P. 822 - 835

Published: April 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.

Language: Английский

Citations

16