Loss of swiss cheese in Neurons Contributes to Neurodegeneration with Mitochondria Abnormalities, Reactive Oxygen Species Acceleration and Accumulation of Lipid Droplets in Drosophila Brain.

Pavel A Melentev,Svetlana V Sarantseva,Mariana I Sliusarenko,Elena V Ryabova,Natalia P Boltneva,Halyna R Shcherbata,Galina F Makhaeva,Darya R Zhmujdina,Nataliya P Matiytsiv,Andriy S Yatsenko,Artem E Komissarov,Nina V Surina,Iryna I Mohylyak,Ekaterina A Ivanova

doi:10.3390/ijms22158275

Abstract

Various neurodegenerative disorders are associated with human NTE/PNPLA6 dysfunction. Mechanisms of neuropathogenesis in these diseases are far from clearly elucidated. Hereditary spastic paraplegia belongs to a type of neurodegeneration associated with NTE/PNLPLA6 and is implicated in neuron death. In this study, we used Drosophila melanogaster to investigate the consequences of neuronal knockdown of swiss cheese (sws)—the evolutionarily conserved ortholog of human NTE/PNPLA6—in vivo. Adult flies with the knockdown show longevity decline, locomotor and memory deficits, severe neurodegeneration progression in the brain, reactive oxygen species level acceleration, mitochondria abnormalities and lipid droplet accumulation. Our results suggest that SWS/NTE/PNPLA6 dysfunction in neurons induces oxidative stress and lipid metabolism alterations, involving mitochondria dynamics and lipid droplet turnover in neurodegeneration pathogenesis. We propose that there is a complex mechanism in neurological diseases such as hereditary spastic paraplegia, which includes a stress reaction, engaging mitochondria, lipid droplets and endoplasmic reticulum interplay.

Highlights

We found the upregulation of antioxidant defense genes in the organism of flies with the neuronal sws knockdown, suggesting that oxidative stress may be a potential consequence of sws downregulation
Since our data demonstrate that the levels of reactive oxygen species (ROS) are increased upon sws deficiency in the brain and it has been shown that elevated ROS levels are often accompanied by abnormalities in the mitochondrial morphology [48,49], we investigated the distribution of mitochondria in the brains of flies with the sws knockdown using the UAS-mito-GFP
We found a small increase in the percentage of 2–3 μm2 lipid droplet (LD) in the knockdown flies compared to the control flies, we concluded that the total elevation of the LD number was not due to the particular LD size overrepresentation, but rather due to LD augmentation of all possible sizes (Figure 7C,D)

Summary

Introduction

The term “hereditary spastic paraplegia” (HSP) is used to describe a group of heterogeneous neurodegenerative disorders, the predominant feature of which is progressive spasticity of the lower extremities due to axonopathy of corticospinal tract neurons [1]. Additional neurological features of the disease include cognitive impairment, ataxia, dysarthria, neuropathy and seizures [2]. HSP affects individuals of various ethnic groups and ages. The combined prevalence of the disease is estimated to be 1.2–9.6 cases per 100,000 individuals worldwide [3]. HSP is one of the most genetically diverse neurological disorders: there are more than 79 identified genes involved in the development of this disease [2]

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