Restoration of Wildtype Neuronal Morphology in Drosophila Spastin Mutants through Alterations in SPG скачать в хорошем качестве

Restoration of Wildtype Neuronal Morphology in Drosophila Spastin Mutants through Alterations in SPG

Abstract- Autosomal Dominant Hereditary spastic paraplegia (AD-HSP) is a neurodegenerative disease in which patients show weak locomotor activity. This condition is frequently caused by the loss of Spastin, a microtubule severing enzyme. When AD-HSP is modeled in Drosophila via loss of Spastin function, adults demonstrate weak locomotor activity while larvae show a unique bunched synaptic bouton morphology at the neuromuscular junction and weaker synaptic signaling. To further elucidate the mechanism of this pathology, we carried out a forward genetic screen and identified loss of p21-activating kinase 3 (Pak3) as a suppressor of the spastin null phenotype. Pak3 has been shown to regulate actin filament dynamics through inhibiting the Rac pathway. Previous experiments showed that loss of Pak3 specifically in gliotactin-expressing cells suppresses the spastin null morphology, implicating Pak3 activity in the subperineurial glia (SPG) as the cells responsible for the spastin mutant pathology. To confirm the role of this cell type, we reduced Pak3 expression in cells expressing Moody, another protein specifically found in subperineurial glia. Through immunostaining and confocal imaging, our result shows that knockdown of Pak3 under the control of the moody promoter has a similar effect as with the gliotactin promoter. Given this promising result, we are interested in understanding the interaction of subperineural glia and neurons spatially and temporally through live-cell imaging.