title: A new model to study neurodegeneration in ataxia oculomotor apraxia type 2.
abstract: Ataxia oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia. Recent evidence suggests that the protein defective in this syndrome, senataxin (SETX), functions in RNA processing to protect the integrity of the genome. To date, only patient-derived lymphoblastoid cells, fibroblasts and SETX knockdown cells were available to investigate AOA2. Recent disruption of the Setx gene in mice did not lead to neurobehavioral defects or neurodegeneration, making it difficult to study the etiology of AOA2. To develop a more relevant neuronal model to study neurodegeneration in AOA2, we derived neural progenitors from a patient with AOA2 and a control by induced pluripotent stem cell (iPSC) reprogramming of fibroblasts. AOA2 iPSC and neural progenitors exhibit increased levels of oxidative damage, DNA double-strand breaks, increased DNA damage-induced cell death and R-loop accumulation. Genome-wide expression and weighted gene co-expression network analysis in these neural progenitors identified both previously reported and novel affected genes and cellular pathways associated with senataxin dysfunction and the pathophysiology of AOA2, providing further insight into the role of senataxin in regulating gene expression on a genome-wide scale. These data show that iPSCs can be generated from patients with the autosomal recessive ataxia, AOA2, differentiated into neurons, and that both cell types recapitulate the AOA2 cellular phenotype. This represents a novel and appropriate model system to investigate neurodegeneration in this syndrome.
authors.affiliation: UQ Centre for Clinical Research (UQCCR), School of Chemistry and Molecular Biosciences and.
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Becherel
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology.
authors.forename: Jane
authors.initials: J
authors.lastname: Sun
authors.affiliation: UQ Centre for Clinical Research (UQCCR), School of Medicine, The University of Queensland, Brisbane, QLD 4029, Australia.
authors.forename: Abrey J
authors.initials: AJ
authors.lastname: Yeo
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology.
authors.forename: Sam
authors.initials: S
authors.lastname: Nayler
authors.affiliation: Department of Neurology and.
authors.forename: Brent L
authors.initials: BL
authors.lastname: Fogel
authors.affiliation: Department of Psychiatry, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA and.
authors.forename: Fuying
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Neurology and Department of Psychiatry, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA and.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Napoli, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Criscuolo
authors.affiliation: Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Napoli, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Michele
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, m.lavin@uq.edu.au e.wolvetang@uq.edu.au.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wolvetang
authors.affiliation: UQ Centre for Clinical Research (UQCCR), m.lavin@uq.edu.au e.wolvetang@uq.edu.au.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D000818:Animals; D017209:Apoptosis; D065150:Cellular Reprogramming; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology; D051379:Mice; D064251:Multifunctional Enzymes; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D018384:Oxidative Stress; D020365:RNA Helicases / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
chemical_list: D064251:Multifunctional Enzymes; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases