Abstract
BackgroundThe ribonuclear protein TDP-43 has been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS), with genetic mutations being linked to the neurological symptoms of the disease. Though alterations in the intracellular distribution of TDP-43 have been observed in skeletal muscles of patients suffering from ALS, it is not clear whether such modifications play an active role in the disease or merely represent an expression of muscle homeostatic mechanisms. Also, the molecular and metabolic pathways regulated by TDP-43 in the skeletal muscle remain largely unknown. Here, we analyze the function of TBPH, the Drosophila melanogaster ortholog of TDP-43, in skeletal muscles.ResultsWe modulated the activity of TDP-43 in Drosophila muscles by means of RNA interference and observed that it is required to promote the formation and growth of neuromuscular synapses. TDP-43 regulated the expression levels of Disc-large (Dlg), and restoring Dlg expression either in skeletal muscles or in motoneurons was sufficient to suppress the locomotive and synaptic defects of TDP-43-null flies. These results were validated by the observation of a decrease in Dlg levels in human neuroblastoma cells and iPSC-differentiated motoneurons derived from ALS patients, suggesting similar mechanisms may potentially be involved in the pathophysiology of the disease.ConclusionsOur results help to unveil the physiological role of TDP-43 in skeletal muscles as well as the mechanisms responsible for the autonomous and non-autonomous behavior of this protein concerning the organization of neuromuscular synapses.
Highlights
The ribonuclear protein TDP-43 has been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS), with genetic mutations being linked to the neurological symptoms of the disease
Its pathology is related to biochemical defects and genetic mutations in the ribonuclear protein (RNP) TDP-43 which have been detected in the great majority of patients and are linked to the neurological symptoms of the disease [1, 2]
We have reported that the endogenous TDP-43 (TBPH) is localized in glial cells in Drosophila melanogaster, where it prevents motoneuron degeneration
Summary
The ribonuclear protein TDP-43 has been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS), with genetic mutations being linked to the neurological symptoms of the disease. A critical role for glia and immune cells has been recognized in the progression of the disease which has been confirmed in different animal models [6,7,8,9,10] 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. 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]. A requirement for TDP-43 has been reported for the in vitro differentiation of C2C12 myoblasts as well as for the regeneration of tibial muscles in vivo [17] Notwithstanding these findings, the molecules and metabolic pathways regulated by TDP-43 in skeletal muscles remain largely unknown.
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