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

TY - JOUR

T1 - Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies

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

N1 - Acceptance date from PDF 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.

PY - 2017/9/13

Y1 - 2017/9/13

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.

KW - insulin signalling

KW - neuroscience

KW - neuronal disorders

U2 - 10.1371/journal.pbio.2001655

DO - 10.1371/journal.pbio.2001655

M3 - Article

VL - 15

SP - e2001655

JO - PLoS Biology

JF - PLoS Biology

SN - 1544-9173

IS - 9

ER -