Glutamic acid metabolism alterations, causes and consequences in ALS

Holodkov, Nikola (2018). Glutamic acid metabolism alterations, causes and consequences in ALS. PhD thesis The Open University.



Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal motor system disease that affects motoneurons causing paralysis and muscular atrophy. Recently, it has been discovered that defects in the protein TDP- 43 were present in most patients that suffer from ALS. Similar modifications in the Drosophila melanogaster conserved protein TBPH reproduced the motor symptoms observed in ALS patients, such as locomotion problems and reduced life expectancy. These phenotypes were mainly originated from alterations in the organization of proteins responsible for synaptic transmission at the neuromuscular junctions (NMJs) in Drosophila.

The objectives of this work are to discover the proteins affected by TBPH function and determine their role in neuronal and non-neuronal tissues. Moreover, I would like to know how they exert their functions and establish whether these pathways are conserved in humans and/or modified in ALS patients. For these experiments, we took advantage of a genome wide proteomic screening to discover that Glutamic Acid Decarboxylase 1 (GAD1), the enzyme that converts Glutamate to GABA, was downregulated in flies lacking the expression of TBPH. We found that this alteration provoked the excessive accumulation of Glutamate, which in turn, promoted defects in the organization of the post-synaptic3 proteins Disc Large and GluRIIA. Pharmacological treatments with Glutamate receptor antagonist Memantine was able to recover the motility problems described in TBPH null larvae including the clustering of the GluRIIA at the terminal membranes. Importantly, we discovered that the suppression of TDP-43 provoked the downregulation of GAD67, the GAD1 homolog protein in human neuroblastoma cell lines and analogous modifications were observed in iPSC-derived motoneurons from ALS patients carrying mutations in TDP-43, uncovering conserved disease mechanisms. In conclusion, we show for the first time a connection between Glutamate metabolism disorders and TDP-43 proteinopathy, two pathological mechanisms of primary importance in ALS.

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