Objective:

We want to see if regulating GSK3β activity could weaken cystic TDP-43 intermediate neuroinflammatory in degenerative diseases.

Background:

TDP-43-positive inclusions have also been reported to be associated with the hippocampal CA1 Lewy-body pathology of familial PD patients bearing a Parkin mutant suggesting that there is likely a link between Parkin and TDP-43. Also, It is known that loss of the nuclear RNA binding protein TAR DNA binding protein-43 (TDP-43) into cytoplasmic inclusions is the strongest correlate to neurodegeneration in frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS). TDP-43, TAF15, and FUS are DNA/RNA binding proteins, and these lead to neurodegenerative disease when inducing cytoplasmic aggregates. Selective expression of TDP-43 in rat astrocytes also leads to non-cell autonomous neuronal toxicity. TDP-43 is ubiquitously expressed in many tissues and cell types, including glial cells of the central nervous system.  Glycogen Synthase Kinase 3β (GSK3β) is a Serine/Threonine protein kinase that phosphorylate either threonine or serine and participates in a variety of cellular processes such glycogen metabolism, gene transcription, apoptosis and microtubule stability.

Design/Methods:

To identify the mechanism of neuroinflammatory induction through over-expression of GSK3β in astrocytes using Shaggy which is the homolog of GSK3β in drosophila model.

Results:

1. GSK3β / Shaggy enzyme activity was increased in TDP-43-induced drosophila degenerative model.

2. Inhibition of Shaggy restored the abnormal wing posture in TDP-43-induced drosophila degenerative model.

3. Inhibition of Shaggy restored the locomotor activity of adult flies in TDP-43-induced drosophila degenerative model.

4. Inhibition of GSK3β restored the neuromuscular junction defects in TDP-43-induced drosophila degenerative model.

5. Cytoplasmic TDP-43 was decreased by the knockdown of GSK3β

6. Astrocyte-derived TDP43 aggregates are spread and propagation to neurons.

Conclusions:

We could see that to regulate GSK3β activity might be weaken cystic TDP-43 intermediate neuroinflammatory in degenerative diseases.