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 |
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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 |
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