Abstract
Alterations in the function of the RNA-binding protein TDP-43 are largely associated with the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease of the human motor system that leads to motoneurons degeneration and reduced life expectancy by molecular mechanisms not well known. In our previous work, we found that the expression levels of the glutamic acid decarboxylase enzyme (GAD1), responsible for converting glutamate to γ-aminobutyric acid (GABA), were downregulated in TBPH-null flies and motoneurons derived from ALS patients carrying mutations in TDP-43, suggesting that defects in the regulation of GAD1 may lead to neurodegeneration by affecting neurotransmitter balance. In this study, we observed that TBPH was required for the regulation of GAD1 pre-mRNA splicing and the levels of GABA in the Drosophila central nervous system (CNS). Interestingly, we discovered that pharmacological treatments aimed to potentiate GABA neurotransmission were able to revert locomotion deficiencies in TBPH-minus flies, revealing novel mechanisms and therapeutic strategies in ALS.
Highlights
A common characteristic shared by several neurodegenerative diseases is the dysfunction of the RNA-binding protein TDP-43, a member of the heterogenous nuclear ribonucleoproteins family 1,2
These results show that TBPH function is required for the proper splicing and expression of the GAD1 pre-mRNA 5’-UTR minigene and strongly suggest that similar alterations may explain the defects detected in the processing of the immature GAD1 mRNA in TBPH-null flies
We found that TBPH has an important role in the modulation of GAD1 mRNA splicing
Summary
A common characteristic shared by several neurodegenerative diseases is the dysfunction of the RNA-binding protein TDP-43, a member of the heterogenous nuclear ribonucleoproteins (hnRNPs) family 1,2. Attentive studies aimed to understand the normal function of TDP-43 and its participation in the mechanisms of neurodegeneration have, became critical to establish the metabolic pathways implicated in TDP-43-mediated neuronal toxicity In this direction we have previously indicated that TDP-43 is required to regulate the synaptic levels of GAD67, the enzyme responsible for converting glutamate to γ-aminobutyric acid (GABA), suggesting that modifications in the glutamate/GABA neurotransmitter balance may affect neuronal survival in TDP-43 perturbed brains 15. Treatments aimed to prevent glutamate mediated excitotoxicity have failed to correct the clinical symptoms of the disease, revealing that different mechanisms might be at work besides the excessive availability of glutamate In support of this hypothesis, it has been reported that GABA levels are reduced in motor cortex of patients with ALS and demonstrated that TDP-43 overexpression increased GAD67 protein levels and GABA release in mouse forebrain 19–22, implying that the synaptic transmission mediated by GABA might be affected or/and may have a role in TDP-43 defective brains. In this study we investigated the mechanisms by which TDP43 regulates the cytoplasmic levels of GAD1 and determined the role of GABA neurotransmission in TDP-43 pathology using Drosophila
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