GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia
| Autor: | Lisa van Ninhuijs, Jean Jacques Martin, Jonathan Baets, Annette Schenck, Erik-Jan Kamsteeg, Bart P.C. van de Warrenburg, Tine Deconinck, Rebecca Schüle, Stephan Züchner, Ilse Eidhof, Peter De Jonghe |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cerebellum medicine.disease_cause Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] whole exome sequencing 0302 clinical medicine genetics [Drosophila Proteins] cellular stress Drosophila Proteins genetics [Genetic Predisposition to Disease] genetics [Nerve Tissue Proteins] genetics [Drosophila melanogaster] GDAP protein Mutation Gene knockdown genetics [Cerebellar Ataxia] biology spasticity Autosomal recessive cerebellar ataxia genetics [Ataxia] Middle Aged Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] medicine.anatomical_structure Drosophila melanogaster Phenotype Gene Knockdown Techniques physiology [Nerve Tissue Proteins] Female physiopathology [Cerebellar Ataxia] medicine.symptom Adult medicine.medical_specialty Ataxia Cerebellar Ataxia physiology [Stress Physiological] methods [Gene Knockdown Techniques] genetics [Stress Physiological] Substantia nigra Genes Recessive Nerve Tissue Proteins physiopathology [Ataxia] 03 medical and health sciences metabolism [Cerebellar Ataxia] Stress Physiological Internal medicine medicine Animals Humans Genetic Predisposition to Disease ddc:610 Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] physiology [Cerebellum] Cerebellar ataxia autosomal recessive cerebellar ataxia Original Articles physiology [Drosophila Proteins] medicine.disease biology.organism_classification physiology [Drosophila melanogaster] 030104 developmental biology Endocrinology nervous system Neurology (clinical) Human medicine 030217 neurology & neurosurgery |
| Zdroj: | Brain Brain, 141, 9, pp. 2592-2604 Brain, 141, 2592-2604 Brain 141(9), 2592-2604 (2018). doi:10.1093/brain/awy198 |
| ISSN: | 0006-8950 |
| DOI: | 10.1093/brain/awy198 |
| Popis: | Eidhofet al. report a new subtype of autosomal recessive cerebellar ataxia caused by mutations inGDAP2, and show thatGdap2 knockdown inDrosophila recapitulates locomotor dysfunction and shortened lifespan. Susceptibility to cellular stress in theGdap2 model suggests altered stress responses as a pathological mechanism. 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 inGDAP2, 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 ofGDAP2 mutations in autosomal recessive cerebellar ataxia pathophysiology, its orthologous gene was investigated in the fruit flyDrosophila melanogaster. Ubiquitous knockdown ofDrosophila 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 inDrosophila andGDAP2 loss-of-function mutations in humans lead to locomotor phenotypes, which may be mediated by altered responses to cellular stress. |
| Databáze: | OpenAIRE |
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