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

Brain. 2018 Sep 1;141(9):2592-2604. doi: 10.1093/brain/awy198.

Ilse Eidhof ¹, Jonathan Baets ² ³ ⁴, Erik-Jan Kamsteeg ¹, Tine Deconinck ² ³, Lisa van Ninhuijs ¹, Jean-Jacques Martin ³, Rebecca Schüle ⁵ ⁶, Stephan Züchner ⁷ ⁸, Peter De Jonghe ² ³ ⁴, Annette Schenck ¹, Bart P van de Warrenburg ⁹

Affiliations

1 Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Centre, GA Nijmegen, The Netherlands.
2 Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.
3 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
4 Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
5 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
6 German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
7 Dr. John T. Macdonald Foundation, Department of Human Genetics, Miami, USA.
8 John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, USA.
9 Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Centre, GC Nijmegen, The Netherlands.

PMID: 30084953 DOI: 10.1093/brain/awy198

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.

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