Mitigating Motor Neuronal Loss in C. elegans Model of ALS8.

Abstract

ALS8 is a late-onset familial autosomal dominant form of Amyotrophic Lateral Sclerosis (ALS) caused by a point mutation (P56S) in the VAPB gene (VAMP associated protein isoform B). Here, we generated two C. elegans models of the disease: a transgenic model where human VAPB wild-type (WT) or P56S mutant was expressed in a subset of motor neurons, and a second model that targeted inducible knockdown of the worm's orthologue, vpr-1. Overexpression of human VAPB in DA neurons caused a backward locomotion defect, axonal misguidance, and premature neuronal death. Knockdown of vpr-1 recapitulated the reduction in VAPB expression associated with sporadic cases of human ALS. It also caused backward locomotion defects as well as an uncoordinated phenotype, and age-dependent, progressive motor neuronal death. Furthermore, inhibiting phosphatidylinositol-4 (PtdIns 4)-kinase activity with PIK-93 reduced the incidence of DA motor neuron loss and improved backward locomotion. This supports the loss of VAPB function in ALS8 pathogenesis and suggests that reducing intracellular PtdIns4P might be an effective therapeutic strategy in delaying progressive loss of motor neurons.

• Authors: Wendy Zhang, Antonio Colavita, Johnny K Ngsee
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 11582 (09 14 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28912432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• VAPB protein, human
• Vesicular Transport Proteins

Topics

• Amyotrophic Lateral Sclerosis (etiology, metabolism, pathology)
• Animals
• Axons (metabolism, pathology)
• Caenorhabditis elegans
• Cell Count
• Disease Models, Animal
• Disease Susceptibility
• Dopaminergic Neurons (metabolism, pathology)
• Gene Expression
• Gene Knockdown Techniques
• Humans
• Mice
• Mice, Transgenic
• Motor Neurons (drug effects, metabolism, pathology)
• Mutation
• Nerve Degeneration (etiology, metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Vesicular Transport Proteins (genetics, metabolism)