TY - JOUR
T1 - Transgenic mice with SCA10 pentanucleotide repeats show motor phenotype and susceptibility to seizure
T2 - A toxic RNA gain-of-function model
AU - White, Misti
AU - Xia, Guangbin
AU - Gao, Rui
AU - Wakamiya, Maki
AU - Sarkar, Partha S.
AU - McFarland, Karen
AU - Ashizawa, Tetsuo
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/3
Y1 - 2012/3
N2 - Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder manifested by ataxia and seizure. SCA10 is caused by a large expansion of an intronic ATTCT pentanucleotide repeat in the ATXN10 gene. We have recently postulated a toxic RNA-mediated gain of function in the pathogenesis of spinal cerebellar ataxia type 10 (SCA10). The spliced intron-9 RNA containing the expanded AUUCU repeat aggregates in SCA10 cells and sequesters hnRNP K. hnRNP K sequestration triggers the translocation of protein kinase Cδ (PKCδ) to mitochondria, leading to activation of caspase-3 and apoptosis. To confirm the toxic RNA-mediated gain of function, we generated a new transgenic mouse model in which the expanded pentanucleotide repeats are constructed in the 3′-untranslated region (3′UTR) to ensure transcription without translation of the repeat. We constructed an artificial transgene containing the SCA10 (ATTCT) 500 track within the 3′UTR of the LacZ gene driven by the rat prion promoter (PrP) and used this to generate a new transgenic mouse model for SCA10. We then examined these mice for neurological phenotypes and histopathological, molecular, and cellular changes. The transgenic mice showed irregular gait and increased seizure susceptibility at the age of 6 months, resembling the clinical phenotype of SCA10. The cerebral cortex, hippocampus, and pontine nuclei showed neuronal loss. The brains of these animals also showed molecular and cellular changes similar to those previously found in an SCA10 cell model. Expression of the expanded SCA10 AUUCU repeat within the 3′UTR of a gene results in neuronal loss with associated gait abnormalities and increased seizure susceptibility phenotypes, which resemble those seen in SCA10 patients. Moreover, these results bolster the idea that the SCA10 disease mechanism is mediated by a toxic RNA gain-of-function mutation of the expanded AUUCU repeat.
AB - Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder manifested by ataxia and seizure. SCA10 is caused by a large expansion of an intronic ATTCT pentanucleotide repeat in the ATXN10 gene. We have recently postulated a toxic RNA-mediated gain of function in the pathogenesis of spinal cerebellar ataxia type 10 (SCA10). The spliced intron-9 RNA containing the expanded AUUCU repeat aggregates in SCA10 cells and sequesters hnRNP K. hnRNP K sequestration triggers the translocation of protein kinase Cδ (PKCδ) to mitochondria, leading to activation of caspase-3 and apoptosis. To confirm the toxic RNA-mediated gain of function, we generated a new transgenic mouse model in which the expanded pentanucleotide repeats are constructed in the 3′-untranslated region (3′UTR) to ensure transcription without translation of the repeat. We constructed an artificial transgene containing the SCA10 (ATTCT) 500 track within the 3′UTR of the LacZ gene driven by the rat prion promoter (PrP) and used this to generate a new transgenic mouse model for SCA10. We then examined these mice for neurological phenotypes and histopathological, molecular, and cellular changes. The transgenic mice showed irregular gait and increased seizure susceptibility at the age of 6 months, resembling the clinical phenotype of SCA10. The cerebral cortex, hippocampus, and pontine nuclei showed neuronal loss. The brains of these animals also showed molecular and cellular changes similar to those previously found in an SCA10 cell model. Expression of the expanded SCA10 AUUCU repeat within the 3′UTR of a gene results in neuronal loss with associated gait abnormalities and increased seizure susceptibility phenotypes, which resemble those seen in SCA10 patients. Moreover, these results bolster the idea that the SCA10 disease mechanism is mediated by a toxic RNA gain-of-function mutation of the expanded AUUCU repeat.
KW - Neurodegenerative disorder
KW - Nucleotide repeat
KW - RNA gain of function
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U2 - 10.1002/jnr.22786
DO - 10.1002/jnr.22786
M3 - Article
C2 - 22065565
AN - SCOPUS:84855877969
SN - 0360-4012
VL - 90
SP - 706
EP - 714
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
IS - 3
ER -