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Local autophagy impairment triggers brain-wide presynaptic remodeling and resilience.

Overview

Authors: David Toppe1, Sheng Huang1,2, Janine Lützkendorf1, Pin-Lian Jiang3, Raquel Suárez-Grimalt1, Alexander Neumann1, Zhiying Zhao1, Péter Lőrincz4,5, Lisa Scheunemann1,2, Gábor Juhász4,5, Fan Liu3,6, Marta Maglione1,2,7, Stephan J Sigrist1,2
ORCID iDs: David Toppe, Sheng Huang, Janine Lützkendorf, Pin-Lian Jiang, Raquel Suárez-Grimalt, Zhiying Zhao, Gábor Juhász, Fan Liu, Marta Maglione, Stephan J Sigrist
  1. Department of Biology, Chemistry, Pharmacy, Institute for Biology/Genetics, Freie Universität Berlin, 14195 Berlin, Germany
  2. NeuroCure Cluster of Excellence, Charité Universitätsmedizin, 10117 Berlin, Germany
  3. Department of Structural Biology, Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany
  4. Institute of Genetics, HUN-REN Biological Research Centre Szeged, Szeged, Hungary
  5. Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary
  6. Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
  7. Department of Biology, Chemistry, Pharmacy, Institute for Chemistry and Biochemistry, SupraFAB, 14195 Berlin, Germany
Institutions: Freie Universität Berlin (Germany); NeuroCure Cluster of Excellence (Germany); Charité - Universitätsmedizin Berlin (Germany); Leibniz-Forschungsinstitut für Molekulare Pharmakologie (Germany); Eötvös Loránd University (Hungary); HUN-REN Szegedi Biológiai Kutatóközpont (Hungary); Institute of Genetics (Hungary)
Journal: The EMBO journal, volume 45, issue 17, pages 6054-6085
Dates: received 6 August 2025; accepted 28 May 2026; published online 8 July 2026; in print September 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s44318-026-00847-4 · PMID 42420489 · PMCID PMC13534471 · OpenAlex W7167670521
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: drosophila (organism), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials, fMRI & imaging
Keywords: Autophagy & Cell Death, Neuroscience
MeSH: Autophagy*, Brain*, Drosophila melanogaster*, Mushroom Bodies*, Neuronal Plasticity*, Presynaptic Terminals*, Animals, Drosophila, Drosophila Proteins (* major topic)
Topic: Neurobiology and Insect Physiology Research (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: European Research Council (101097053); Deutsche Forschungsgemeinschaft (495407463, 447288260, 390688087); Hungarian Academy of Sciences (LP2023-6, LP2022-13); Leibniz-Wettbewerb (P70/2018)
Citations: not cited yet (Europe PMC); 106 references in the paper

Abstract

Neural circuits must remain functionally stable while adapting to changing demands and levels of stress. While this balance is thought to rely on plasticity programs integrating molecular and activity-dependent signals, mechanistic models of how such adaptations are orchestrated remain limited. Here, we show that impairment of autophagy in the Drosophila mushroom body (MB) induces brain-wide, post-transcriptional remodeling of presynaptic active zones, characterized by increased expression levels of active zone scaffold proteins, reduced abundance of calcium channel subunits, and elevated levels of Shaker-type potassium channels. This remodeling promotes organismal resilience, as reflected by increased sleep and extended lifespan. Mechanistically, early-life activation of this program is sufficient to extend lifespan, identifying synaptic remodeling as a causal driver of adaptive responses. MB-specific autophagy disruption further leads to non-cell autonomous accumulation of autophagic substrates across the brain, consistent with a system-level proteostatic imbalance in which degradative pathways remain active, but appear insufficient to match cargo load. Our findings identify autophagy in the mushroom body as a key regulator of brain-wide synaptic architecture and resilience, and establish a genetically tractable model for how local proteostatic impairment can trigger adaptive, system-level circuit remodeling.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

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Data availability

The data and resources that support the findings of this study are available from the corresponding author upon reasonable request. Source data underlying the main and EV figures are uploaded alongside this article. RAW RNA-sequencing data were uploaded to the ArrayExpress database under the accession number E-MTAB-17037 (http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-17037/) (https://www.ebi.ac.uk/biostudies/arrayexpress/studies/E-MTAB-17037). RAW proteomics data were uploaded to the PRIDE database under the project accession number PXD076163 (http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD076163) (https://www.ebi.ac.uk/pride/archive/projects/PXD076163/).

The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44318-026-00847-4 (https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44318-026-00847-4).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 2 keywords, 9 MeSH terms, 4 funders, 106 references.

Cite

This paper

Toppe, D., Huang, S., Lützkendorf, J., Jiang, P.-L., Suárez-Grimalt, R., Neumann, A., Zhao, Z., Lőrincz, P., Scheunemann, L., Juhász, G., Liu, F., Maglione, M., & Sigrist, S. J. (2026). Local autophagy impairment triggers brain-wide presynaptic remodeling and resilience. The EMBO journal, 45(17), 6054-6085. https://doi.org/10.1038/s44318-026-00847-4

BibTeX

@article{toppe2026local,
author = {Toppe, David and Huang, Sheng and Lützkendorf, Janine and Jiang, Pin-Lian and Suárez-Grimalt, Raquel and Neumann, Alexander and Zhao, Zhiying and Lőrincz, Péter and Scheunemann, Lisa and Juhász, Gábor and Liu, Fan and Maglione, Marta and Sigrist, Stephan J},
title = {{Local autophagy impairment triggers brain-wide presynaptic remodeling and resilience}},
journal = {The EMBO journal},
year = {2026},
month = jul,
volume = {45},
number = {17},
pages = {6054--6085},
publisher = {Nature Publishing Group},
issn = {0261-4189},
doi = {10.1038/s44318-026-00847-4},
url = {https://doi.org/10.1038/s44318-026-00847-4},
pmid = {42420489},
pmcid = {PMC13534471}
}

RIS

TY - JOUR
AU - Toppe, David
AU - Huang, Sheng
AU - Lützkendorf, Janine
AU - Jiang, Pin-Lian
AU - Suárez-Grimalt, Raquel
AU - Neumann, Alexander
AU - Zhao, Zhiying
AU - Lőrincz, Péter
AU - Scheunemann, Lisa
AU - Juhász, Gábor
AU - Liu, Fan
AU - Maglione, Marta
AU - Sigrist, Stephan J
TI - Local autophagy impairment triggers brain-wide presynaptic remodeling and resilience
T2 - The EMBO journal
J2 - EMBO J
PY - 2026
DA - 2026/07/08
VL - 45
IS - 17
SP - 6054
EP - 6085
SN - 0261-4189
PB - Nature Publishing Group
DO - 10.1038/s44318-026-00847-4
UR - https://doi.org/10.1038/s44318-026-00847-4
LA - en
ER -

CSL-JSON

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