Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies

Hrvoje Augustin; Kieran McGourty; Marcus J.  Allen; Sirisha Kudumala Madem; Jennifer Adcot; Fiona Kerr; Chi Tung Wong; Alec Vincent; Tanja Godenschwege; Emmanuel Boucrot; Linda Partridge

doi:10.1371/journal.pbio.2001655

Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies

Hrvoje Augustin, Kieran McGourty, Marcus J. Allen, Sirisha Kudumala Madem, Jennifer Adcot, Fiona Kerr, Chi Tung Wong, Alec Vincent, Tanja Godenschwege, Emmanuel Boucrot, Linda Partridge^*

^*Corresponding author for this work

Biological and Biomedical Sciences

Research output: Contribution to journal › Article

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Abstract

Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the “insulin paradox”). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders.

Original language	English
Article number	e2001655
Number of pages	25
Journal	PLoS Biology
Volume	15
Issue number	9
DOIs	https://doi.org/10.1371/journal.pbio.2001655
Publication status	Published - 13 Sep 2017

Keywords

insulin signalling
neuroscience
neuronal disorders

Documents and Links

10.1371/journal.pbio.2001655

Augustin, H. et al (2017) Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies
© 2017 Augustin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Final published version, 7.33 MBLicence: CC BY

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Augustin, H., McGourty, K., Allen, M. J., Madem, S. K., Adcot, J., Kerr, F., Wong, C. T., Vincent, A., Godenschwege, T., Boucrot, E., & Partridge, L. (2017). Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies. PLoS Biology, 15(9), [e2001655]. https://doi.org/10.1371/journal.pbio.2001655

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title = "Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies",

abstract = "Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the “insulin paradox”). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders.",

keywords = "insulin signalling, neuroscience, neuronal disorders",

author = "Hrvoje Augustin and Kieran McGourty and Allen, {Marcus J.} and Madem, {Sirisha Kudumala} and Jennifer Adcot and Fiona Kerr and Wong, {Chi Tung} and Alec Vincent and Tanja Godenschwege and Emmanuel Boucrot and Linda Partridge",

note = "Acceptance from web page - ELL 5/5/20 Funding: Wellcome Trust Strategic Award to L.P. (grant number WT098565). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. David Phillips Research Fellowship to E.B. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Lister Institute for Preventive Medicine prize to E.B. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The National Institute for Neurological Disease and Stroke grant to T.G. (grant number R15NS090043). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Alzheimer's Research UK (ARUK) programme grant to L.P. (grant number ART-PG2009-4). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Jupiter Life Sciences Initiative to S.K.M. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ",

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Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies. / Augustin, Hrvoje; McGourty, Kieran; Allen, Marcus J. ; Madem, Sirisha Kudumala; Adcot, Jennifer; Kerr, Fiona; Wong, Chi Tung; Vincent, Alec; Godenschwege, Tanja; Boucrot, Emmanuel; Partridge, Linda.

In: PLoS Biology, Vol. 15, No. 9, e2001655, 13.09.2017.

Research output: Contribution to journal › Article

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AU - Augustin, Hrvoje

AU - McGourty, Kieran

AU - Allen, Marcus J.

AU - Madem, Sirisha Kudumala

AU - Adcot, Jennifer

AU - Kerr, Fiona

AU - Wong, Chi Tung

AU - Vincent, Alec

AU - Godenschwege, Tanja

AU - Boucrot, Emmanuel

AU - Partridge, Linda

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PY - 2017/9/13

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N2 - Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the “insulin paradox”). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders.

AB - Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the “insulin paradox”). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders.

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