Apache is a neuronal player in autophagy required for retrograde axonal transport of autophagosomes.
Autophagosomes
/ metabolism
Autophagy
/ physiology
Animals
Neurons
/ metabolism
Axonal Transport
/ physiology
Mice
Cells, Cultured
TOR Serine-Threonine Kinases
/ metabolism
Microtubule-Associated Proteins
/ metabolism
Sequestosome-1 Protein
/ metabolism
Receptor, trkB
/ metabolism
Signal Transduction
Nerve Tissue Proteins
/ metabolism
Presynaptic Terminals
/ metabolism
AP-2
Amphisome
LC3
Retrograde trafficking
Synapse
Torin1
TrkB
mTOR
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
05 Oct 2024
05 Oct 2024
Historique:
received:
29
11
2023
accepted:
29
08
2024
revised:
19
08
2024
medline:
6
10
2024
pubmed:
6
10
2024
entrez:
5
10
2024
Statut:
epublish
Résumé
Neurons are dependent on efficient quality control mechanisms to maintain cellular homeostasis and function due to their polarization and long-life span. Autophagy is a lysosomal degradative pathway that provides nutrients during starvation and recycles damaged and/or aged proteins and organelles. In neurons, autophagosomes constitutively form in distal axons and at synapses and are trafficked retrogradely to the cell soma to fuse with lysosomes for cargo degradation. How the neuronal autophagy pathway is organized and controlled remains poorly understood. Several presynaptic endocytic proteins have been shown to regulate both synaptic vesicle recycling and autophagy. Here, by combining electron, fluorescence, and live imaging microscopy with biochemical analysis, we show that the neuron-specific protein APache, a presynaptic AP-2 interactor, functions in neurons as an important player in the autophagy process, regulating the retrograde transport of autophagosomes. We found that APache colocalizes and co-traffics with autophagosomes in primary cortical neurons and that induction of autophagy by mTOR inhibition increases LC3 and APache protein levels at synaptic boutons. APache silencing causes a blockade of autophagic flux preventing the clearance of p62/SQSTM1, leading to a severe accumulation of autophagosomes and amphisomes at synaptic terminals and along neurites due to defective retrograde transport of TrkB-containing signaling amphisomes along the axons. Together, our data identify APache as a regulator of the autophagic cycle, potentially in cooperation with AP-2, and hypothesize that its dysfunctions contribute to the early synaptic impairments in neurodegenerative conditions associated with impaired autophagy.
Identifiants
pubmed: 39367928
doi: 10.1007/s00018-024-05441-7
pii: 10.1007/s00018-024-05441-7
doi:
Substances chimiques
TOR Serine-Threonine Kinases
EC 2.7.11.1
Microtubule-Associated Proteins
0
Sequestosome-1 Protein
0
Receptor, trkB
EC 2.7.10.1
Nerve Tissue Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
416Informations de copyright
© 2024. The Author(s).
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