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

Autor: Chi Tung Wong, Alec J. Vincent, Linda Partridge, Jennifer Adcott, Marcus J. Allen, Emmanuel Boucrot, Hrvoje Augustin, Fiona Kerr, Sirisha Kudumala Madem, Kieran McGourty, Tanja A. Godenschwege
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Aging
Physiology
medicine.medical_treatment
Cell Membranes
GTPase
Biochemistry
Nervous System
Synaptic Transmission
Connexins
Endocrinology
0302 clinical medicine
Escape Reaction
Neural Pathways
Medicine and Health Sciences
Insulin
Biology (General)
biology
Drosophila Melanogaster
General Neuroscience
Gap junction
Gap Junctions
Animal Models
Cell biology
Insects
Electrophysiology
Experimental Organism Systems
Drosophila
Female
Anatomy
Junctional Complexes
Cellular Structures and Organelles
General Agricultural and Biological Sciences
Research Article
Cell Physiology
medicine.medical_specialty
Cell type
Arthropoda
QH301-705.5
Neurophysiology
Innexin
Neurotransmission
Research and Analysis Methods
bcs
General Biochemistry
Genetics and Molecular Biology

03 medical and health sciences
Model Organisms
Somatomedins
Internal medicine
medicine
Animals
Diabetic Endocrinology
Endocrine Physiology
General Immunology and Microbiology
Growth factor
Insulin Signaling
fungi
Organisms
Biology and Life Sciences
Membrane Proteins
Cell Biology
Invertebrates
Hormones
Neuroanatomy
Insulin receptor
030104 developmental biology
rab GTP-Binding Proteins
Synapses
biology.protein
Physiological Processes
Organism Development
030217 neurology & neurosurgery
Neuroscience
Developmental Biology
Zdroj: PLoS Biol
PLoS Biology
PLoS Biology, Vol 15, Iss 9, p e2001655 (2017)
ISSN: 1545-7885
Popis: 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.
Author summary Insulin and insulin-like growth factors play an important role in the nervous system development and function. Reduced insulin signaling, however, can improve symptoms of neurodegenerative diseases in different model organisms and protect against age-associated decline in neuronal function extending lifespan. Here, we analyze the effects of genetically attenuated insulin signaling on the escape response pathway in the fruit fly Drosophila melanogaster. This simple neuronal circuit is dominated by electrical synapses composed of the gap junctional shaking-B protein, which allows for the transfer of electrical impulses between cells. Transmission through the circuit is known to slow down with age. We show that this functional decline is prevented by systemic or circuit-specific suppression of insulin signaling due to the preservation of the number of gap junctional proteins in aging animals. Our experiments in a human cell culture system reveal increased membrane targeting of gap junctional proteins via small proteins Rab4 and Rab11 under reduced insulin conditions. We also find that increasing the level of these recycling-mediating proteins in flies preserves the escape response circuit output in old flies and suggests ways of improving the function of neuronal circuits dominated by electrical synapses during aging.
Databáze: OpenAIRE