Autophagy lipidation machinery regulates axonal microtubule dynamics but is dispensable for survival of mammalian neurons.

Negrete-Hurtado, A; Overhoff, M; Bera, S; De Bruyckere, E; Schätzmüller, K; Kye, MJ; Qin, C; Lammers, M; Kondylis, V; Neundorf, I; Kononenko, NL

Autophagy lipidation machinery regulates axonal microtubule dynamics but is dispensable for survival of mammalian neurons.

Negrete-Hurtado, A Overhoff, M Bera, S De Bruyckere, E Schätzmüller, K Kye, MJ Qin, C Lammers, M Kondylis, V Neundorf, I Kononenko, NL

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Publisher:: Springer Science and Business Media LLC
Publication Type:: Journal Article
Citation:: Nature communications, 2020, 11, (1)
Issue Date:: 2020-03-24

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Field	Value	Language
dc.contributor.author	Negrete-Hurtado, A
dc.contributor.author	Overhoff, M
dc.contributor.author	Bera, S
dc.contributor.author	De Bruyckere, E
dc.contributor.author	Schätzmüller, K
dc.contributor.author	Kye, MJ
dc.contributor.author	Qin, C
dc.contributor.author	Lammers, M
dc.contributor.author	Kondylis, V
dc.contributor.author	Neundorf, I
dc.contributor.author	Kononenko, NL
dc.date.accessioned	2020-10-23T04:30:11Z
dc.date.available	2020-02-25
dc.date.available	2020-10-23T04:30:11Z
dc.date.issued	2020-03-24
dc.identifier.citation	Nature communications, 2020, 11, (1)
dc.identifier.issn	2041-1723
dc.identifier.issn	2041-1723
dc.identifier.uri	http://hdl.handle.net/10453/143505
dc.description.abstract	Neurons maintain axonal homeostasis via employing a unique organization of the microtubule (MT) cytoskeleton, which supports axonal morphology and provides tracks for intracellular transport. Abnormal MT-based trafficking hallmarks the pathology of neurodegenerative diseases, but the exact mechanism regulating MT dynamics in axons remains enigmatic. Here we report on a regulation of MT dynamics by AuTophaGy(ATG)-related proteins, which previously have been linked to the autophagy pathway. We find that ATG proteins required for LC3 lipid conjugation are dispensable for survival of excitatory neurons and instead regulate MT stability via controlling the abundance of the MT-binding protein CLASP2. This function of ATGs is independent of their role in autophagy and requires the active zone protein ELKS1. Our results highlight a non-canonical role of ATG proteins in neurons and suggest that pharmacological activation of autophagy may not only promote the degradation of cytoplasmic material, but also impair axonal integrity via altering MT stability.
dc.format	Electronic
dc.language	eng
dc.publisher	Springer Science and Business Media LLC
dc.relation.ispartof	Nature communications
dc.relation.isbasedon	10.1038/s41467-020-15287-9
dc.rights	This is a post-peer-review, pre-copyedit version of an article published in Nature communications. The final authenticated version is available online at: https://dx.doi.org/10.1038/s41467-020-15287-9.	en_US
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Axons
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	Microtubules
dc.subject.mesh	Animals
dc.subject.mesh	Animals, Newborn
dc.subject.mesh	Mice
dc.subject.mesh	rab GTP-Binding Proteins
dc.subject.mesh	Microtubule-Associated Proteins
dc.subject.mesh	Nerve Tissue Proteins
dc.subject.mesh	Recombinant Proteins
dc.subject.mesh	Cell Survival
dc.subject.mesh	Autophagy
dc.subject.mesh	Lipid Metabolism
dc.subject.mesh	Gene Knockout Techniques
dc.subject.mesh	Primary Cell Culture
dc.subject.mesh	Autophagy-Related Protein 5
dc.subject.mesh	Axons
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	Microtubules
dc.subject.mesh	Animals
dc.subject.mesh	Animals, Newborn
dc.subject.mesh	Mice
dc.subject.mesh	rab GTP-Binding Proteins
dc.subject.mesh	Microtubule-Associated Proteins
dc.subject.mesh	Nerve Tissue Proteins
dc.subject.mesh	Recombinant Proteins
dc.subject.mesh	Cell Survival
dc.subject.mesh	Autophagy
dc.subject.mesh	Lipid Metabolism
dc.subject.mesh	Gene Knockout Techniques
dc.subject.mesh	Primary Cell Culture
dc.subject.mesh	Autophagy-Related Protein 5
dc.subject.mesh	Animals
dc.subject.mesh	Animals, Newborn
dc.subject.mesh	Autophagy
dc.subject.mesh	Autophagy-Related Protein 5
dc.subject.mesh	Axons
dc.subject.mesh	Cell Survival
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	Gene Knockout Techniques
dc.subject.mesh	Lipid Metabolism
dc.subject.mesh	Mice
dc.subject.mesh	Microtubule-Associated Proteins
dc.subject.mesh	Microtubules
dc.subject.mesh	Nerve Tissue Proteins
dc.subject.mesh	Primary Cell Culture
dc.subject.mesh	Recombinant Proteins
dc.subject.mesh	rab GTP-Binding Proteins
dc.title	Autophagy lipidation machinery regulates axonal microtubule dynamics but is dispensable for survival of mammalian neurons.
dc.type	Journal Article
utslib.citation.volume	11
utslib.location.activity	England
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
dc.date.updated	2020-10-23T04:29:34Z
pubs.issue	1
pubs.publication-status	Published
pubs.volume	11
utslib.citation.issue	1

Abstract:

Neurons maintain axonal homeostasis via employing a unique organization of the microtubule (MT) cytoskeleton, which supports axonal morphology and provides tracks for intracellular transport. Abnormal MT-based trafficking hallmarks the pathology of neurodegenerative diseases, but the exact mechanism regulating MT dynamics in axons remains enigmatic. Here we report on a regulation of MT dynamics by AuTophaGy(ATG)-related proteins, which previously have been linked to the autophagy pathway. We find that ATG proteins required for LC3 lipid conjugation are dispensable for survival of excitatory neurons and instead regulate MT stability via controlling the abundance of the MT-binding protein CLASP2. This function of ATGs is independent of their role in autophagy and requires the active zone protein ELKS1. Our results highlight a non-canonical role of ATG proteins in neurons and suggest that pharmacological activation of autophagy may not only promote the degradation of cytoplasmic material, but also impair axonal integrity via altering MT stability.

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http://hdl.handle.net/10453/143505