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.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is an adult-onset disease characterized by progressive degeneration and loss of motoneurons followed by the atrophic denervation of the skeletal muscles [1]
We found that the expression of TBPH-RNA interference (RNAi) with repoGAL4 induced a strong reduction in the neuromuscular area covered by the glia compared with controls (Fig. 1B,C)
We observed that these phenotypes were accompanied by a significant reduction in the evoked junction potentials (EJPs) registered in TBPH silenced glia compared with controls (Fig. 1G), indicating that the synaptic transmission was altered in the neuromuscular junctions (NMJ)
Summary
Amyotrophic Lateral Sclerosis (ALS) is an adult-onset disease characterized by progressive degeneration and loss of motoneurons followed by the atrophic denervation of the skeletal muscles [1]. Recent histological analysis revealed the presence of insoluble TDP-43 in glial tissues as well, suggesting that different cell types may contribute to the degenerative process observed in ALS [3,4] On this basis, it has been proposed that perturbations in neuron–glia interactions could lead to neurodegeneration by different cell-autonomous and non-autonomous mechanisms [5,6,7,8]. It has been proposed that perturbations in neuron–glia interactions could lead to neurodegeneration by different cell-autonomous and non-autonomous mechanisms [5,6,7,8] In agreement with this hypothesis, experiments performed in Drosophila models showed that modulations of the endogenous TDP-43 protein (TBPH) in the glia provoked locomotive defects and a reduction in life span, implying that the alterations in these tissues may affect neuronal activity and initiate the neurological symptoms of the disease [9,10]. We analyze the function of TBPH in the Drosophila glia and show that is essential for axon wrapping and glutamate receptor clustering in vivo
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