Swiss Cheese, Drosophila Ortholog of Hereditary Spastic Paraplegia Gene NTE, Maintains Neuromuscular Junction Development and Microtubule Network

Abstract

Neuropathy target esterase (NTE) is a molecular target for the organophosphorus compound-induced delayed neuropathy (OPIDN) and also one of the genetic factors responsible for the development of the hereditary spastic paraplegia (HSP), characterized by axon degeneration of motoneurons causing progressive lower-limb spastic paralysis. Both HSP and OPIDN are characterized by the distal axonopathy. The molecular mechanisms underlying the axonopathy involved in HSP and OPIDN are poorly understood. In order to have a beter understanding of the mechanisms that NTE is involved in, we used one of the homologs, human NTE. Swiss cheese (sws) is a Drosophila melanogaster ortholog of NTE with 39% homology. Mutations in sws as it was shown before lead to age-dependent neurodegeneration, structure alteration of glia cells, and reduced insect life span. To study SWS functions, we used the system of the third-instar larval neuromuscular junctions of D. melanogaster. In this study, we show that mutations in sws (sws 1 and sws 76−1) and SWS knockdown alter neuromuscular junction's morphology and synaptic microtubules organization.

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

“…A plethora of experiments shows that the ablation of HSP-related genes infers mitochondrial dynamics in axons, however, sometimes indirectly, through an endoplasmic reticulum state [ 106 , 107 , 108 , 109 , 110 ]. Furthermore, we have previously found SWS to be present presynaptically in larval neuromuscular junctions, and its dysfunction altered their organization, influencing mitochondria distribution [ 111 ].…”

Drosophila Glia: Models for Human Neurodevelopmental and Neurodegenerative Disorders

“…The mutations in sws develop axonal and glial pathology and neuronal apoptosis. Additionally, the SWS protein was recently shown to play a role in the maintenance of neuromuscular function development and microtubule networks [88]. The sws gene is the ortholog of the neuropathy target esterase (NTE) gene, which is one of the genetic factors responsible for the development of hereditary spastic paraplegia [88].…”

“…Additionally, the SWS protein was recently shown to play a role in the maintenance of neuromuscular function development and microtubule networks [88]. The sws gene is the ortholog of the neuropathy target esterase (NTE) gene, which is one of the genetic factors responsible for the development of hereditary spastic paraplegia [88]. In both vertebrates and invertebrates, the insulating of axons by glial processes is the only way to increase the conduction velocity of electrical impulses.…”

Morpho-Functional Consequences of Swiss Cheese Knockdown in Glia of Drosophila melanogaster

“…It was also initially shown that glial hyperwrapping exists in sws mutants [ 9 ]. In our previous work, we found that sws was mainly detected on the surface of the ventral nerve cord, in abdominal nerves, and presynaptically at the neuro-muscular junctions of PNS of the 3rd instar larvae [ 40 ].…”

“…This leads to locomotor deficits due to both neuronal and glial dysfunction. For instance, neuromuscular junction alterations are accompanied with by an active zone decline and postsynaptic reaction to this deterioration due to the neuronal sws KD in Drosophila [ 40 ]. The human sws orthologue is associated with several syndromes of the spasticity—ataxia continuum caused by neurodegeneration in the spinal cord, cerebellum, and/or pituitary gland [ 67 ].…”