A De Novo RAPGEF2 Variant Identified in a Sporadic Amyotrophic Lateral Sclerosis Patient Impairs Microtubule Stability and Axonal Mitochondria Distribution.
- Author:
Keunjung HEO
1
;
Su Min LIM
;
Minyeop NAHM
;
Young Eun KIM
;
Ki Wook OH
;
Hwan Tae PARK
;
Chang Seok KI
;
Seung Hyun KIM
;
Seungbok LEE
Author Information
- Publication Type:Original Article
- Keywords: Amyotrophic lateral sclerosis; Whole exome sequencing; RAPGEF2; Missense mutation; Microtubules; Mitochondria
- MeSH: Amyotrophic Lateral Sclerosis*; Axons*; Drosophila; Exome; Fibroblasts; Histone Deacetylases; Humans; Microtubules*; Mitochondria*; Motor Neurons; Mutant Proteins; Mutation, Missense; Neurodegenerative Diseases; Neuromuscular Junction; Skin; Synapses
- From:Experimental Neurobiology 2018;27(6):550-563
- CountryRepublic of Korea
- Language:English
- Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is frequently linked to microtubule abnormalities and mitochondrial trafficking defects. Whole exome sequencing (WES) of patient-parent trios has proven to be an efficient strategy for identifying rare de novo genetic variants responsible for sporadic ALS (sALS). Using a trio-WES approach, we identified a de novo RAPGEF2 variant (c.4069G>A, p.E1357K) in a patient with early-onset sALS. To assess the pathogenic effects of this variant, we have used patient-derived skin fibroblasts and motor neuron-specific overexpression of the RAPGEF2-E1357K mutant protein in Drosophila. Patient fibroblasts display reduced microtubule stability and defective microtubule network morphology. The intracellular distribution, ultrastructure, and function of mitochondria are also impaired in patient cells. Overexpression of the RAPGEF2 mutant in Drosophila motor neurons reduces the stability of axonal microtubules and disrupts the distribution of mitochondria to distal axons and neuromuscular junction (NMJ) synapses. We also show that the recruitment of the pro-apoptotic protein BCL2-associated X (BAX) to mitochondria is significantly increased in patient fibroblasts compared with control cells. Finally, increasing microtubule stability through pharmacological inhibition of histone deacetylase 6 (HDAC6) rescues defects in the intracellular distribution of mitochondria and BAX. Overall, our data suggest that the RAPGEF2 variant identified in this study can drive ALS-related pathogenic effects through microtubule dysregulation.
