Biogenesis and reformation of synaptic vesicles DOI Creative Commons

Svenja Bolz,

Volker Haucke

The Journal of Physiology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 5, 2024

Abstract Communication within the nervous system relies on calcium‐triggered release of neurotransmitter molecules by exocytosis synaptic vesicles (SVs) at defined active zone sites. While decades research have provided detailed insight into molecular machinery for SV fusion, much less is known about mechanisms that form functional SVs during development synapses and control local reformation following in mature system. Here we review current state knowledge field, focusing pathways implicated formation axonal transport precursor organelles involved nerve terminals neurons. We discuss open questions outline perspectives future research. image

Language: Английский

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
Protocol for live imaging of axonal transport in iPSC-derived iNeurons DOI
Dan Dou, Erika L.F. Holzbaur, C. Alexander Boecker

et al.

STAR Protocols, Journal Year: 2025, Volume and Issue: 6(1), P. 103556 - 103556

Published: Jan. 12, 2025

Language: Английский

Citations

0
The spectrum of lysosomal stress and damage responses: from mechanosensing to inflammation DOI Creative Commons
Ori Scott, Ekambir Saran, Spencer A. Freeman

et al.

EMBO Reports, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Abstract Cells and tissues turn over their aged damaged components in order to adapt a changing environment maintain homeostasis. These functions rely on lysosomes, dynamic heterogeneous organelles that play essential roles nutrient redistribution, metabolism, signaling, gene regulation, plasma membrane repair, immunity. Because of metabolic fluctuations pathogenic threats, lysosomes must the short long term functionality. In response such challenges, deploy variety mechanisms prevent breaching escape contents, including pathogen-associated molecules hydrolases. While transient permeabilization lysosomal can have acute beneficial effects, supporting inflammation antigen cross-presentation, sustained or repeated perforations adverse transcriptional consequences lead cell death. This review outlines factors contributing stress damage perception, as well remedial processes aimed at addressing disruptions. We conclude plays widespread human physiology pathology, understanding manipulation which open door novel therapeutic strategies.

Language: Английский

Citations

0
Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain DOI Creative Commons
Vijay Pal Singh,

Marissa Menard,

Geidy E. Serrano

et al.

Acta Neuropathologica Communications, Journal Year: 2023, Volume and Issue: 11(1)

Published: Dec. 18, 2023

Abstract Autosomal dominant pathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease (PD). The most common mutation, G2019S-LRRK2, increases the activity of LRRK2 causing hyper-phosphorylation its substrates. One these substrates, Rab10, is phosphorylated at a conserved Thr73 residue (pRab10), and one abundant Rab GTPases expressed various tissues. involvement Rab10 neurodegenerative disease, including both PD Alzheimer’s makes pinpointing cellular subcellular localization pRab10 brain an important step understanding functional role, how post-translational modifications could impact function. To establish specificity antibodies to form specific antisense oligonucleotides were intraventricularly injected into brains mice. Further, knock out induced neurons, differentiated from human pluripotent stem cells used test antibody specificity. amplify weak immunofluorescence signal pRab10, tyramide amplification was utilized. cortex, striatum substantia nigra pars compacta. Immunofluorescence for increased G2019S-LRRK2 knockin Neurons, astrocytes, microglia oligodendrocytes all showed expression. While colocalized with endoplasmic reticulum, lysosome trans-Golgi network markers, did not localize organelles. However, overlap markers presynaptic terminal mouse α-synuclein. Results this study suggest are areas cell types tested study, but enriched terminal. As substrate, may affect mediated membrane trafficking neurons disease.

Language: Английский

Citations

5
Soma-centered control of synaptic autophagy by Rab39-regulated anterograde trafficking of Atg9 DOI Open Access
Ayse Kilic,

Dirk Vandekerkhove,

Sabine Kuenen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 21, 2024

Presynaptic terminals can be located far from the neuronal cell body and are thought to independently regulate protein organelle turnover. In this work, we report a soma-centered mechanism that regulates autophagy-driven turnover at distant presynaptic in Drosophila. We show system is regulated by Rab39, whose human homolog mutated Parkinson's disease. Although Rab39 localized soma, its loss of function causes increased autophagy terminals, resulting faster synaptic neurodegeneration. Using large-scale unbiased genetic modifier screen, identified genes encoding cytoskeletal axonal organizing proteins, including Shortstop (Shot), as suppressors autophagy. demonstrate controls Shot- Unc104/KIF1a-mediated transport autophagy-related Atg9 vesicles synapses. Under starvation conditions, soma shifts localization endosomes lysosomes, thereby controlling availability for trafficking Our findings indicate Rab39-mediated orchestrates cross-compartmental abundance

Language: Английский

Citations

1
Effects of bound nucleotides on the secondary structure, thermal stability, and phosphorylation of Rab3A DOI Creative Commons
Genta Ito, Taisuke Tomita,

Naoko Utsunomiya‐Tate

et al.

Biochemical and Biophysical Research Communications, Journal Year: 2024, Volume and Issue: 723, P. 150199 - 150199

Published: May 30, 2024

Rab3A is a member of the Rab GTPase family involved in synaptic vesicle trafficking. Recent evidence has demonstrated that phosphorylated by leucine-rich repeat kinase 2 (LRRK2) implicated both familial and sporadic forms Parkinson's disease (PD), an abnormal increase phosphorylation been proposed as cause PD. Despite potential importance PD pathogenesis, its structural information limited effects bound nucleotides on biophysical biochemical properties remain unclear. Here, we show GDP-bound preferentially LRRK2 compared with GTP-bound Rab3A. The secondary structure Rab3A, measured circular dichroism (CD) spectroscopy, revealed resistant to heat-induced denaturation at pH 7.4 or 9.0 regardless bound. In contrast, underwent 5.0 lower temperature form than form. unfolding was studied differential scanning fluorimetry, which showed significantly higher highest 7.4. These results suggest unusual thermal stability under physiologically relevant conditions influence LRRK2.

Language: Английский

Citations

0
Biogenesis and reformation of synaptic vesicles DOI Creative Commons

Svenja Bolz,

Volker Haucke

The Journal of Physiology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 5, 2024

Abstract Communication within the nervous system relies on calcium‐triggered release of neurotransmitter molecules by exocytosis synaptic vesicles (SVs) at defined active zone sites. While decades research have provided detailed insight into molecular machinery for SV fusion, much less is known about mechanisms that form functional SVs during development synapses and control local reformation following in mature system. Here we review current state knowledge field, focusing pathways implicated formation axonal transport precursor organelles involved nerve terminals neurons. We discuss open questions outline perspectives future research. image

Language: Английский

Citations

0