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.

TDP-43 promotes the formation of neuromuscular synapses through the regulation of Disc-large expression in Drosophila skeletal muscles

“…In this respect, we have reported that the endogenous TDP-43 (TBPH) is localized in glial cells in Drosophila melanogaster, where it prevents motoneuron degeneration. This supports the idea that ALS may have a nonneuronal origin [11]. In consonance with this hypothesis, pathological modifications of TDP-43 have been found in the skeletal muscles of patients with different neuromuscular diseases such as inclusion body myositis (IBM) and sporadic, familial forms of ALS [12].…”

TDP-43 regulates the expression levels of Disc-large in skeletal muscles to promote the assemble of the neuromuscular synapses in Drosophila

“…In this direction, the critical role of the glia and immune cells in the progression of the disease has been recently described in ALS individuals and confirmed in different animal models (Boillée et al, 2006;Brettschneider et al, 2012;Diaper et al, 2013;Ince et al, 2011;Tong et al, 2013). Regarding to that, we have reported that the endogenous TDP-43 protein in Drosophila melanogaster (TBPH) localizes in glial cells and is required in these tissues to prevent motoneurons degeneration supporting the idea that ALS may present a non-neuronal origin [10]. In consonance with this hypothesis, pathological modifications in TDP-43 were also detected in the skeletal muscles of patients suffering of different neuromuscular diseases alike inclusion body myositis (IBM) or sporadic and familial forms of ALS [12].…”

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

“…In transgenic rats with restricted neuronal expression of an ALS-linked mutant TDP-43 or FUS, lipocalin-2 is upregulated in reactive astrocytes and may have a direct neurotoxic effect [85]. Likely, glial and neuronal cells respond in a different manner to the toxic accumulation of TDP-43, but a growing body of evidence suggests an important role of TDP-43 dysfunction in astrocytes in the context of motor neuron degeneration in ALS [45, 86–88]. Interestingly, TDP-43 is present in the eosinophilic inclusions characteristically found within astrocytes in the brain of Alexander disease patients [89], suggesting that primary alteration of TDP-43 biology within astrocytes can lead to neurodegeneration.…”