понедељак, 10 децембар 2018 09:49

Glutamic acid metabolism alterations, causes and consequences in ALS

Предавач: др Никола Холодков

Време: 13. 12. 2018. у 13.00

Место: Библиотека ИБИСС



Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal motor system disease that affects motoneurons causing paralysis and atrophy in all body. Due to the heterogenous nature of the disease and the uncharacterized molecular processes, diagnosis is challenging, and treatment is limited and inefficient. Recently, it has been discovered that the vast majority of ALS patients suffer from TDP-43 proteinopathy. Normally, this protein is localized in the nucleus where it is involved in RNA metabolism. In ALS, however, TDP-43 is mislocalized from the nucleus to the cytoplasm, where it harbours important post-translational modifications and is part of cytosolic inclusions. Drosophila melanogaster TBPH/TDP-43 loss-of-function model resembles the motor symptoms observed in ALS patients, such as locomotion problems and reduced life expectancy. These manifestations can be reconducted to clustering alteration of proteins responsible for synaptic signalling at drosophila’s neuro-muscular junctions (NMJs).

The objective of this work was to discover how TBPH promoted the alteration of synaptic proteins. More specifically we investigated which were the proteins affected by TBPH, what was their role in neuronal and non-neuronal tissues, how did they exert its function on the synapse and whether these pathways were conserved in humans and ALS patients. Thus, we took advantage of wide screen proteomic analysis and discovered 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 provoked excessive levels of Glutamate which in turn promoted clustering alteration of post-synaptic proteins Disc Large and GluRIIA. Moreover, treatment with Glutamate receptor antagonists Memantine rescued the motility problems in TBPH null larva and GluRIIA clustering after TBPH silencing in neurons. Also, we identified that GABA was strongly downregulated in brains of TBPH null flies and silencing of GABA Receptors (GABARs) in neurons provoked strong degeneration of motility in flies with reduced levels of neuronal TBPH expression. Importantly, we discovered that TDP-GAD relationship was conserved in human neuroblastoma cells and that iPSC derived from TDP-ALS patients had downregulated levels of GAD65 and GAD67, the homologues of GAD1 in humans. In conclusion, we showed for the first time a connection between Glutamate metabolism disorders and TDP-43 proteinopathy, two pathological mechanism of primary importance in ALS.


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