Rab6-mediated polarized transport of synaptic vesicle precursors is essential for the establishment of neuronal polarity and brain formation DOI Creative Commons
Yu Zhang, Masataka Kunii,

Manabu Taniguchi

et al.

Journal of Neuroscience, Journal Year: 2024, Volume and Issue: 44(27), P. e2334232024 - e2334232024

Published: June 3, 2024

Neurons are highly polarized cells that composed of a single axon and multiple dendrites. Axon-dendrite polarity is essential for proper tissue formation brain functions. Intracellular protein transport plays an important role in the establishment neuronal polarity. However, regulatory mechanism remains unclear. Here, we show Rab6, small GTPase acts on regulation intracellular vesicular trafficking, key roles polarization development. Central nervous system-specific Rab6a/b double knock-out (Rab6 DKO) mice both sexes exhibit severe dysplasia neocortex cerebellum. In Rab6 DKO neocortex, impaired axonal extension neurons results hypoplasia intermediate zone. vitro, deletion Rab6a Rab6b cultured from causes abnormal accumulation synaptic vesicle precursors (SVPs) adjacent to Golgi apparatus, which leads defects loss axon-dendrite Moreover, significant expansion lysosomes soma neurons. Overall, our reveal Rab6-mediated SVPs crucial subsequent formation.

Language: Английский

Optogenetics at the presynapse DOI
Benjamin R. Rost, Jonas Wietek, Ofer Yizhar

et al.

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(8), P. 984 - 998

Published: July 14, 2022

Language: Английский

Citations

71
Phosphatidylinositol 3,5-bisphosphate facilitates axonal vesicle transport and presynapse assembly DOI
Filiz Sila Rizalar, Max Thomas Lucht, Astrid G. Petzoldt

et al.

Science, Journal Year: 2023, Volume and Issue: 382(6667), P. 223 - 230

Published: Oct. 12, 2023

Neurons relay information via specialized presynaptic compartments for neurotransmission. Unlike conventional organelles, the apparatus characterizing neuronal presynapse must form de novo. How components neurotransmission are transported and assembled is poorly understood. Our results show that rare late endosomal signaling lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P

Language: Английский

Citations

25
Liprin-α proteins are master regulators of human presynapse assembly DOI Creative Commons
Berta Marcó de la Cruz, Joaquín Campos, Angela Molinaro

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(4), P. 629 - 642

Published: March 12, 2024

ABSTRACT The formation of mammalian synapses entails the precise alignment presynaptic release sites with postsynaptic receptors but how nascent cell–cell contacts translate into assembly specializations remains unclear. Guided by pioneering work in invertebrates, we hypothesized that synapses, liprin-α proteins directly link trans -synaptic initial to downstream steps. Here show that, human neurons lacking all four isoforms, synaptic are formed recruitment active zone components and accumulation vesicles is blocked, resulting ‘empty’ boutons loss transmission. Interactions cell adhesion molecules either LAR-RPTP family or neurexins via CASK required localize sites. Liprin-α subsequently recruits a direct interaction ELKS proteins. Thus, terminals governed hierarchical sequence events which critical step.

Language: Английский

Citations

12
Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies DOI Open Access

Fan Wang,

Xueheng Xie,

Xiaoyan Xing

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(16), P. 9381 - 9381

Published: Aug. 19, 2022

Stroke is one of the leading causes death and disability in world, which ischemia accounts for majority. There growing evidence changes synaptic connections neural network functions brain stroke patients. Currently, studies on these neurobiological alterations mainly focus principle glutamate excitotoxicity, corresponding neuroprotective strategies are limited to blocking overactivation ionic receptors. Nevertheless, it disappointing that treatments often fail because unspecificity serious side effects tested drugs clinical trials. Thus, prevention treatment stroke, finding developing new targets intervention still goal research this field. In review, we whole processes glutamatergic transmission highlight pathological underlying each link help develop potential therapeutic ischemic damage. These include: (1) controlling or extra-synaptic release glutamate, (2) selectively action receptor NMDAR subunit, (3) increasing metabolism, reuptake blood, (4) regulating system by GABA receptors microbiota-gut-brain axis. Based latest findings, expected promote a substantial understanding complex signal transduction mechanism, thereby providing excellent neuroprotection direction human (IS).

Language: Английский

Citations

37
SynBot is an open-source image analysis software for automated quantification of synapses DOI Creative Commons
Justin T Savage, J.J. Ramirez, W. Christopher Risher

et al.

Cell Reports Methods, Journal Year: 2024, Volume and Issue: 4(9), P. 100861 - 100861

Published: Sept. 1, 2024

Language: Английский

Citations

8
Presynaptic perspective: Axonal transport defects in neurodevelopmental disorders DOI Creative Commons
Gui-Jing Xiong, Zu‐Hang Sheng

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(6)

Published: April 3, 2024

Disruption of synapse assembly and maturation leads to a broad spectrum neurodevelopmental disorders. Presynaptic proteins are largely synthesized in the soma, where they packaged into precursor vesicles transported distal axons ensure precise maintenance presynapses. Due their morphological features, neurons face challenges delivery presynaptic cargos nascent boutons. Thus, targeted axonal transport is vital build functional synapses. A growing number mutations genes encoding machinery have been linked Emerging lines evidence started uncover mechanisms underlying defects, thus broadening view disorders beyond postsynaptic mechanisms. In this review, we discuss perspectives by focusing on impaired disturbed We also potential strategies for restoring as an early therapeutic intervention.

Language: Английский

Citations

6
Polybasic Patches in Both C2 Domains of Synaptotagmin-1 Are Required for Evoked Neurotransmitter Release DOI Open Access

Zhenyong Wu,

Lu Ma,

Nicholas A. Courtney

et al.

Journal of Neuroscience, Journal Year: 2022, Volume and Issue: 42(30), P. 5816 - 5829

Published: June 14, 2022

Synaptotagmin-1 (Syt1) is a vesicular calcium sensor required for synchronous neurotransmitter release, composed of single-pass transmembrane domain linked to two C2 domains (C2A and C2B) that bind calcium, acidic lipids, SNARE proteins drive fusion the synaptic vesicle with plasma membrane. Despite its essential role, how Syt1 couples entry release poorly understood. Calcium binding C2B critical additionally binds complex. The C2A also function, but it not clear why. Here, we asked what feature may be responsible functional role compared this analogous in C2B. We focused on highly conserved poly-lysine patches located sides (K189-192) (K324-327). tested effects charge-neutralization mutations either region (Syt1K189-192A Syt1K326-327A) side by determine their relative contributions function cultured cortical neurons from mice sex single-molecule experiments. Combining electrophysiological recordings optical tweezers measurements probe dynamic single domain–membrane interactions, show both polybasic contribute membrane binding, are evoked release. size readily releasable pool rate spontaneous were unaffected, so likely specifically synchronization suggest these cooperative increasing overall affinity negatively charged membranes facilitating SIGNIFICANCE STATEMENT Its tandem cytosolic How leads unclear. regions cooperatively, membranes.

Language: Английский

Citations

20
LRK-1/LRRK2 and AP-3 regulate trafficking of synaptic vesicle precursors through active zone protein SYD-2/Liprin-α DOI Creative Commons
Sravanthi S. P. Nadiminti,

Shirley B. Dixit,

Neena Ratnakaran

et al.

PLoS Genetics, Journal Year: 2024, Volume and Issue: 20(5), P. e1011253 - e1011253

Published: May 9, 2024

Synaptic vesicle proteins (SVps) are transported by the motor UNC-104/KIF1A. We show that SVps travel in heterogeneous carriers C . elegans neuronal processes, with some SVp co-transporting lysosomal (SV-lysosomes). LRK-1/LRRK2 and clathrin adaptor protein complex AP-3 play a critical role sorting of away from each other at SV-lysosomal intermediate trafficking compartment. Both lacking SV-lysosomes dependent on UNC-104/KIF1A for their transport. In lrk-1 mutants, both can axons absence UNC-104, suggesting LRK-1 plays an important to enable UNC-104 transport synaptic proteins. Additionally, acts upstream regulates its membrane localization. complex, become more UNC-104-SYD-2/Liprin-α Therefore, SYD-2 link events likely through interaction UNC-104. further mistrafficking into dendrite apb-3 mutants depends SYD-2, regulating recruitment AP-1/UNC-101. concert AP complexes ensure polarized & SVps.

Language: Английский

Citations

4
A Functional Dissection of the mRNA and Locally Synthesized Protein Population in Neuronal Dendrites and Axons DOI
J. Pérez, Claudia M. Fusco, Erin M. Schuman

et al.

Annual Review of Genetics, Journal Year: 2021, Volume and Issue: 55(1), P. 183 - 207

Published: Aug. 30, 2021

Neurons are characterized by a complex morphology that enables the generation of subcellular compartments with unique biochemical and biophysical properties, such as dendrites, axons, synapses. To sustain these different carry wide array elaborate operations, neurons express diverse repertoire gene products. Extensive regulation at both messenger RNA (mRNA) protein levels allows for differentiation well numerous forms plasticity in response to variable stimuli. Among multiple mechanisms control cellular functions, mRNA translation is manipulated regulate where when emerges. Interestingly, transcriptomic translatomic profiles dendrites axons have revealed population only partially predicts local this relation significantly varies between groups. Here, we describe space occupies within large molecular regulatory complexity neurons, contrast other modes regulation. We then discuss specialized organization mRNAs neuronal compartments, transcriptome. Finally, features functional implications locally correlated—and anticorrelated—mRNA-protein relations under baseline conditions during synaptic plasticity.

Language: Английский

Citations

26
The Rab11-regulated endocytic pathway and BDNF/TrkB signaling: Roles in plasticity changes and neurodegenerative diseases DOI

Guillermo Moya‐Alvarado,

Miguel V. Guerra,

R. Tiburcio

et al.

Neurobiology of Disease, Journal Year: 2022, Volume and Issue: 171, P. 105796 - 105796

Published: June 18, 2022

Language: Английский

Citations

18