A new model to study neurodegeneration in ataxia oculomotor apraxia type 2

Becherel, Olivier J., Sun, Jane, Yeo, Abrey J., Nayler, Sam, Fogel, Brent L., Gao, Fuying, Coppola, Giovanni, Criscuolo, Chiara, De Michele, Giuseppe, Wolvetang, Ernst and Lavin, Martin F. (2015) A new model to study neurodegeneration in ataxia oculomotor apraxia type 2. Human Molecular Genetics, 24 20: 5759-5774. doi:10.1093/hmg/ddv296

Author Becherel, Olivier J.
Sun, Jane
Yeo, Abrey J.
Nayler, Sam
Fogel, Brent L.
Gao, Fuying
Coppola, Giovanni
Criscuolo, Chiara
De Michele, Giuseppe
Wolvetang, Ernst
Lavin, Martin F.
Title A new model to study neurodegeneration in ataxia oculomotor apraxia type 2
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
Publication date 2015-08-01
Year available 2015
Sub-type Article (original research)
DOI 10.1093/hmg/ddv296
Volume 24
Issue 20
Start page 5759
End page 5774
Total pages 16
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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Created: Tue, 15 Sep 2015, 20:04:58 EST by Roheen Gill on behalf of UQ Centre for Clinical Research