Glial TDP-43 regulates axon wrapping, GluRIIA clustering and fly motility by autonomous and non-autonomous mechanisms.

Abstract

Alterations in the glial function of TDP-43 are becoming increasingly associated with the neurological symptoms observed in Amyotrophic Lateral Sclerosis (ALS), however, the physiological role of this protein in the glia or the mechanisms that may lead to neurodegeneration are unknown. To address these issues, we modulated the expression levels of TDP-43 in the Drosophila glia and found that the protein was required to regulate the subcellular wrapping of motoneuron axons, promote synaptic growth and the formation of glutamate receptor clusters at the neuromuscular junctions. Interestingly, we determined that the glutamate transporter EAAT1 mediated the regulatory functions of TDP-43 in the glia and demonstrated that genetic or pharmacological compensations of EAAT1 activity were sufficient to modulate glutamate receptor clustering and locomotive behaviors in flies. The data uncovers autonomous and non-autonomous functions of TDP-43 in the glia and suggests new experimentally based therapeutic strategies in ALS.

• Authors: Giulia Romano, Chiara Appocher, Michele Scorzeto, Raffaella Klima, Francisco E Baralle, Aram Megighian, Fabian Feiguin
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 21 Pg. 6134-45 (Nov 01 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 26276811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press.

Chemical References

• DNA-Binding Proteins
• Drosophila Proteins
• Receptors, Glutamate
• TARDBP protein, human
• TBPH protein, Drosophila
• glutamate receptor III, Drosophila

Topics

• Amyotrophic Lateral Sclerosis (metabolism)
• Animals
• Animals, Genetically Modified
• Axons (physiology)
• DNA-Binding Proteins (genetics, physiology)
• Drosophila
• Drosophila Proteins (metabolism, physiology)
• Female
• Locomotion
• Male
• Motor Activity
• Motor Neurons (physiology)
• Neuroglia (physiology)
• Receptors, Glutamate (metabolism)