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Age-dependent degeneration of an identified adult leg motor neuron in a Drosophila SOD1 model of ALS.


ABSTRACT: Mutations in superoxide dismutase 1 (SOD1) cause familial amyotrophic lateral sclerosis (ALS) in humans. ALS is a neurodegenerative disease characterized by progressive motor neuron loss leading to paralysis and inevitable death in affected individuals. Using a gene replacement strategy to introduce disease mutations into the orthologous Drosophila sod1 (dsod1) gene, here, we characterize changes at the neuromuscular junction using longer-lived dsod1 mutant adults. Homozygous dsod1H71Y/H71Y or dsod1null/null flies display progressive walking defects with paralysis of the third metathoracic leg. In dissected legs, we assessed age-dependent changes in a single identified motor neuron (MN-I2) innervating the tibia levitator muscle. At adult eclosion, MN-I2 of dsod1H71Y/H71Y or sod1null/null flies is patterned similar to wild-type flies indicating no readily apparent developmental defects. Over the course of 10?days post-eclosion, MN-I2 shows an overall reduction in arborization with bouton swelling and loss of the post-synaptic marker discs-large (dlg) in mutant dsod1 adults. In addition, increases in polyubiquitinated proteins correlate with the timing and extent of MN-I2 changes. Because similar phenotypes are observed between flies homozygous for either dsod1H71Y or dsod1null alleles, we conclude these NMJ changes are mainly associated with sod loss-of-function. Together these studies characterize age-related morphological and molecular changes associated with axonal retraction in a Drosophila model of ALS that recapitulate an important aspect of the human disease.This article has an associated First Person interview with the first author of the paper.

SUBMITTER: Agudelo A 

PROVIDER: S-EPMC7595701 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Age-dependent degeneration of an identified adult leg motor neuron in a <i>Drosophila</i> SOD1 model of ALS.

Agudelo Anthony A   St Amand Victoria V   Grissom Lindsey L   Lafond Danielle D   Achilli Toni T   Sahin Asli A   Reenan Robert R   Stilwell Geoff G  

Biology open 20201021 10


Mutations in superoxide dismutase 1 (SOD1) cause familial amyotrophic lateral sclerosis (ALS) in humans. ALS is a neurodegenerative disease characterized by progressive motor neuron loss leading to paralysis and inevitable death in affected individuals. Using a gene replacement strategy to introduce disease mutations into the orthologous <i>Drosophila sod1</i> (<i>dsod1</i>) gene, here, we characterize changes at the neuromuscular junction using longer-lived <i>dsod1</i> mutant adults. Homozygou  ...[more]

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