Related Experiment Video
Updated: Jun 15, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
The ALS-associated KIF5A P986L variant is not pathogenic for Drosophila motoneurons
Sophie Layalle1, Franck Aimond2, Véronique Brugioti2
1Institute for Neurosciences Montpellier, Institut National de la Santé et de la Recherche Médicale, Université Montpellier, Montpellier, France. sophie.layalle@inserm.fr.
Abstract:
Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by the death of motoneurons. Several mutations in the KIF5A gene have been identified in patients with ALS. Some mutations affect the splicing sites of exon 27 leading to its deletion (Δ27 mutation). KIF5A Δ27 is aggregation-prone and pathogenic for motoneurons due to a toxic gain of function. Another mutation found to be enriched in ALS patients is a proline/leucine substitution at position 986 (P986L mutation). Bioinformatic analyses strongly suggest that this variant is benign. Our study aims to conduct functional studies in Drosophila to classify the KIF5A P986L variant. When expressed in motoneurons, KIF5A P986L does not modify the morphology of larval NMJ or the synaptic transmission. In addition, KIF5A P986L is uniformly distributed in axons and does not disturb mitochondria distribution. Locomotion at larval and adult stages is not affected by KIF5A P986L. Finally, both KIF5A WT and P986L expression in adult motoneurons extend median lifespan compared to control flies. Altogether, our data show that the KIF5A P986L variant is not pathogenic for motoneurons and may represent a hypomorphic allele, although it is not causative for ALS.
Insights
The KIF5A P986L variant, found in amyotrophic lateral sclerosis (ALS) patients, does not harm motor neurons in Drosophila models. This suggests KIF5A P986L is not a cause of ALS.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron death.
- Mutations in the KIF5A gene are associated with ALS, including exon deletions and missense variants.
- The KIF5A P986L variant is enriched in ALS patients, but its pathogenicity is uncertain.
Purpose of the Study:
- To functionally characterize the KIF5A P986L variant in a Drosophila melanogaster model.
- To determine if KIF5A P986L exhibits pathogenic properties in motor neurons.
Main Methods:
- Expression of wild-type (WT) and P986L mutant KIF5A in Drosophila motor neurons.
- Assessment of larval neuromuscular junction (NMJ) morphology and synaptic transmission.
- Analysis of axonal transport, mitochondrial distribution, and locomotion.
- Evaluation of median lifespan in adult flies.
Main Results:
- KIF5A P986L expression did not alter NMJ morphology or synaptic transmission.
- Axonal distribution and mitochondrial transport remained unaffected by KIF5A P986L.
- Locomotion was not impaired in flies expressing KIF5A P986L.
- Both WT and P986L KIF5A extended median lifespan in adult flies.
Conclusions:
- The KIF5A P986L variant is not pathogenic for Drosophila motor neurons.
- KIF5A P986L may represent a hypomorphic allele rather than a causative mutation for ALS.
- Further investigation is needed to fully understand the role of KIF5A variants in ALS pathogenesis.
More Related Videos
09:34Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
10:41Why Quantification Matters: Characterization of Phenotypes at the Drosophila Larval Neuromuscular Junction
Published on: May 12, 2016
Related Concept Videos
02:32Exon Recombination
Exon shuffling follows “splice frame rules.” Each exon...
02:41Lethal Alleles
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...