Depletion of ESCRT ameliorates APP‐induced AD‐like symptoms in <i>Drosophila</i>

Zhuang, Luming; Li, Chenglin; Peng, Fei; Xue, Elleen; Li, Wenzhe; Sun, Xinyue; Chen, Ping; Zhou, Qian; Xue, Lei

doi:10.1002/jcp.31035

Cited by 5 publications

(1 citation statement)

References 48 publications

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“…Importantly, our results do not rule out signaling functions for Syt4 or Evi/Wg EVs in other contexts or neuronal cell types, or for other EV cargoes. For example, ESCRT disruption suppresses the pathological functions of APP in Drosophila, perhaps due to its reduced propagation in EVs (Zhuang et al, 2023). Indeed, extensive evidence supports signaling and pathological functions for neuronal EVs in multiple contexts (Gassama and Favereaux, 2021;Lizarraga-Valderrama and Sheridan, 2021;Schnatz et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

ESCRT disruption provides evidence against signaling functions for synaptic exosomes

Dresselhaus

Harris

Koles

et al. 2023

Preprint

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Exosomes are membrane-bound vesicles released by many cells including neurons, carrying cargoes involved in signaling and disease. It has been unclear whether exosomes promote intercellular signaling in vivo or serve primarily to dispose of unwanted cargo. This is because manipulations of exosome cargo expression or traffic often result in their depletion from the donor cell, making it difficult to distinguish whether these cargoes act cell-autonomously or through transcellular transfer. Exosomes arise when multivesicular endosomes fuse with the plasma membrane, releasing their intralumenal vesicles outside the cell. We show that loss of multivesicular endosome-generating ESCRT (endosomal sorting complex required for transport) machinery disrupts release of exosome cargoes from Drosophila motor neurons, without depleting them from the donor presynaptic terminal. Cargoes and autophagic vacuoles accumulate in presynaptic terminals, suggesting that compensatory autophagy follows endosome dysfunction. Surprisingly, exosome cargoes Synaptotagmin-4 (Syt4) and Evenness Interrupted (Evi) retain many of their signaling activities upon ESCRT depletion, despite being trapped in presynaptic terminals. Thus, these cargoes may not require intercellular transfer, and instead are likely to function cell autonomously in the motor neuron. Our results indicate that synaptic exosome release depends on ESCRT, and serves primarily as a proteostatic mechanism for at least some cargoes.

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Section: Discussionmentioning

confidence: 99%

ESCRT disruption provides evidence against signaling functions for synaptic exosomes

Dresselhaus

Harris

Koles

et al. 2023

Preprint

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Nuclear pore complex and nucleocytoplasmic transport disruption in neurodegeneration

Cristi,

Rapuri,

Coyne

2023

FEBS Letters

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Nuclear pore complexes (NPCs) play a critical role in maintaining the equilibrium between the nucleus and cytoplasm, enabling bidirectional transport across the nuclear envelope, and are essential for proper nuclear organization and gene regulation. Perturbations in the regulatory mechanisms governing NPCs and nuclear envelope homeostasis have been implicated in the pathogenesis of several neurodegenerative diseases. The ESCRT‐III pathway emerges as a critical player in the surveillance and preservation of well‐assembled, functional NPCs, as well as nuclear envelope sealing. Recent studies have provided insights into the involvement of nuclear ESCRT‐III in the selective reduction of specific nucleoporins associated with neurodegenerative pathologies. Thus, maintaining quality control of the nuclear envelope and NPCs represents a pivotal element in the pathological cascade leading to neurodegenerative diseases. This review describes the constituents of the nuclear‐cytoplasmic transport machinery, encompassing the nuclear envelope, NPC, and ESCRT proteins, and how their structural and functional alterations contribute to the development of neurodegenerative diseases.

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Gp93 inhibits unfolded protein response‐mediated c‐Jun N‐terminal kinase activation and cell invasion

Xu,

Wu,

et al. 2024

Journal Cellular Physiology

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In eukaryotes, Hsp90B1 serves as a vital chaperonin, facilitating the accurate folding of proteins. Interestingly, Hsp90B1 exhibits contrasting roles in the development of various types of cancers, although the underlying reasons for this duality remain enigmatic. Through the utilization of the Drosophila model, this study unveils the functional significance of Gp93, the Drosophila ortholog of Hsp90B1, which hitherto had limited reported developmental functions. Employing the Drosophila cell invasion model, we elucidated the pivotal role of Gp93 in regulating cell invasion and modulating c‐Jun N‐terminal kinase (JNK) activation. Furthermore, our investigation highlights the involvement of the unfolded protein response‐associated IRE1/XBP1 pathway in governing Gp93 depletion‐induced, JNK‐dependent cell invasion. Collectively, these findings not only uncover a novel molecular function of Gp93 in Drosophila, but also underscore a significant consideration pertaining to the testing of Hsp90B1 inhibitors in cancer therapy.

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Depletion of ESCRT ameliorates APP‐induced AD‐like symptoms in Drosophila

Cited by 5 publications

References 48 publications

ESCRT disruption provides evidence against signaling functions for synaptic exosomes

ESCRT disruption provides evidence against signaling functions for synaptic exosomes

Nuclear pore complex and nucleocytoplasmic transport disruption in neurodegeneration

Gp93 inhibits unfolded protein response‐mediated c‐Jun N‐terminal kinase activation and cell invasion

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