GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia

Ilse Eidhof, Jonathan Baets, Erik Jan Kamsteeg, Tine Deconinck, Lisa Van Ninhuijs, Jean Jacques Martin, Rebecca Schüle, Stephan L Zuchner, Peter De Jonghe, Annette Schenck, Bart P. Van De Warrenburg

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Autosomal recessive cerebellar ataxias are a group of rare disorders that share progressive degeneration of the cerebellum and associated tracts as the main hallmark. Here, we report two unrelated patients with a new subtype of autosomal recessive cerebellar ataxia caused by biallelic, gene-disruptive mutations in GDAP2, a gene previously not implicated in disease. Both patients had onset of ataxia in the fourth decade. Other features included progressive spasticity and dementia. Neuropathological examination showed degenerative changes in the cerebellum, olive inferior, thalamus, substantia nigra, and pyramidal tracts, as well as tau pathology in the hippocampus and amygdala. To provide further evidence for a causative role of GDAP2 mutations in autosomal recessive cerebellar ataxia pathophysiology, its orthologous gene was investigated in the fruit fly Drosophila melanogaster. Ubiquitous knockdown of Drosophila Gdap2 resulted in shortened lifespan and motor behaviour anomalies such as righting defects, reduced and uncoordinated walking behaviour, and compromised flight. Gdap2 expression levels responded to stress treatments in control flies, and Gdap2 knockdown flies showed increased sensitivity to deleterious effects of stressors such as reactive oxygen species and nutrient deprivation. Thus, Gdap2 knockdown in Drosophila and GDAP2 loss-of-function mutations in humans lead to locomotor phenotypes, which may be mediated by altered responses to cellular stress.

Original languageEnglish (US)
Pages (from-to)2592-2604
Number of pages13
JournalBrain
Volume141
Issue number9
DOIs
StatePublished - Sep 1 2018

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Keywords

  • autosomal recessive cerebellar ataxia
  • cellular stress
  • Drosophila melanogaster
  • spasticity
  • whole exome sequencing

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Eidhof, I., Baets, J., Kamsteeg, E. J., Deconinck, T., Van Ninhuijs, L., Martin, J. J., Schüle, R., Zuchner, S. L., De Jonghe, P., Schenck, A., & Van De Warrenburg, B. P. (2018). GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia. Brain, 141(9), 2592-2604. https://doi.org/10.1093/brain/awy198