Transgenic Models of Spinocerebellar Ataxia Type 10: Modeling a Repeat Expansion Disorder
Abstract
:1. Introduction
1.1. SCA10—An Autosomal Dominant, Neurodegenerative Disorder
1.2. Phenotypic Variability of SCA10
2. Repeat Purity as a Phenotypic Modifier?
3. SCA10 as an RNA Mediated Gain-of-Function Mutation
4. Prior Animal Models of SCA10
4.1. SCA10 Intronic Model
SCA10 patient fibroblasts | Transgenic Mice (Eno2-β-globin intron-LacZ) | Transgenic Mice (Prnp-LacZ-3'UTR) | ||
Mouse Strain | n.a. | C57/Bl/6 | FVB/N | |
Repeat Expansion | 1,000 repeats | 500 repeats | 500 repeats | |
Molecular Phenotypes | LacZ mRNA (via qRT-PCR) | n.a. | n.d. | Throughout brain including cerebellum, also outside of brain |
β-gal protein (via immunostaining) | n.a. | n.d. | Lowest in Purkinje Cells of cerebellum, highest in cerebral cortex and pontine nuclei | |
RNA foci (via FISH) | Yes | Yes, at 3 mon & 6 mon in cortex | Yes, at 3 & 6 months in cortex, pontine and hippocampusNot found at 1 month | |
hnRNP K/RNA foci colocalization (via FISH/immunostaining) | Yes | Yes, at 3 mon & 6 mon in cortex | Yes at 6 months in pontine nuclei & hippocampus | |
Apoptosis (via TUNEL) | n.d. | n.d. | None in hippocampal CA3 | |
Gliosis? (via GFAP immunostaining) | n.a. | n.d. | None in hippocampal CA3 | |
Splicing Defects of hnRNP K target exons | Increased use of exon 6A vs exon 6B in TPM2 | n.d. | n.d. | |
PKCδ mitochondrial localization (via colocalization &/or fractionation) | Increased | Increased | Increased | |
hnRNPK-PKCδ interactions (via co-IP) | Decreased | n.d. | n.d. | |
Pathological phenotypes | Neuropathological | n.a. | n.d. | Neuronal loss in hippocampal CA3 region; no obvious neuronal loss in cerebellum |
Other findings | n.a. | n.d. | Increased glycogen accumulation in frontal lobe starting at 3 months, increasing by 6 months, nearly 100% of neurons by 18 months | |
Behavioral Phenotypes | Open Field at 6 months | n.a. | n.d. | Traveled lesser distance and at slower speed with fewer crossings |
Footprint Analysis at 6 months | n.a. | n.d. | Step length shortened with step width variability and awkward hindlimb movements | |
Rotarod, fixed speed at 6 months | n.a. | n.d. | normal | |
Rotarod, accelerated at 6 months | n.a. | n.d. | normal | |
Hindlimb Clasp at 3 & 6 months | n.a. | n.d. | Yes, all by 6 months | |
About half by 3 months | ||||
Other, abnormal at 6 months | n.a. | Decreased reproductive fitness | Decreased grooming, abnormal whisker twitch reflex | |
Other, Normal at 6 months | n.a. | n.d. | Eye blink, ear twitch & righting reflexes | |
Home Cage Behavior | n.a. | n.d. | Demonstrate preconvulsant behaviors | |
Seizure susceptibility | n.a. | n.d. | Seizures at low doses of PTZ; full tonic-clonic seizures and death at higher doses |
4.2. SCA10 3' UTR Model
5. Improvements for the Future
6. Rigorous Assessment to Compare Behavioral Phenotypes
7. Conclusions
Acknowledgements
References
- Alonso, E.; Martínez‐Ruano, L.; de Biase, I.; Mader, C.; Ochoa, A.; Yescas, P.; Gutiérrez, R.; White, M.; Ruano, L.; Fragoso‐Benítez, M. Distinct distribution of autosomal dominant spinocerebellar ataxia in the Mexican population. Mov. Disord. 2007, 22, 1050–1053. [Google Scholar] [CrossRef]
- Matsuura, T.; Yamagata, T.; Burgess, D.L.; Rasmussen, A.; Grewal, R.P.; Watase, K.; Khajavi, M.; McCall, A.E.; Davis, C.F.; Zu, L. Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat. Genet. 2000, 26, 191–194. [Google Scholar] [CrossRef]
- Matsuura, T.; Fang, P.; Pearson, C.E.; Jayakar, P.; Ashizawa, T.; Roa, B.B.; Nelson, D.L. Interruptions in the expanded ATTCT repeat of spinocerebellar ataxia type 10: Repeat purity as a disease modifier? Am. J. Hum. Genet. 2006, 78, 125–129. [Google Scholar] [CrossRef]
- Raskin, S.; Ashizawa, T.; Teive, H.A.; Arruda, W.O.; Fang, P.; Gao, R.; White, M.C.; Werneck, L.C.; Roa, B. Reduced penetrance in a Brazilian family with spinocerebellar ataxia type 10. Arch. Neurol. 2007, 64, 591–594. [Google Scholar]
- Lin, X.; Ashizawa, T. SCA10 and ATTCT repeat expansion: Clinical features and molecular aspects. Cytogenet. Genome Res. 2003, 100, 184–188. [Google Scholar] [CrossRef]
- Grewal, R.P.; Achari, M.; Matsuura, T.; Durazo, A.; Tayag, E.; Zu, L.; Pulst, S.M.; Ashizawa, T. Clinical features and ATTCT repeat expansion in spinocerebellar ataxia type 10. Arch. Neurol. 2002, 59, 1285–1290. [Google Scholar] [CrossRef]
- Rasmussen, A.; Matsuura, T.; Ruano, L.; Yescas, P.; Ochoa, A.; Ashizawa, T.; Alonso, E. Clinical and genetic analysis of four Mexican families with spinocerebellar ataxia type 10. Ann. Neurol. 2001, 50, 234–239. [Google Scholar] [CrossRef]
- Teive, H.A.; Roa, B.B.; Raskin, S.; Fang, P.; Arruda, W.O.; Neto, Y.C.; Gao, R.; Werneck, L.C.; Ashizawa, T. Clinical phenotype of Brazilian families with spinocerebellar ataxia 10. Neurology 2004, 63, 1509–1512. [Google Scholar]
- Gatto, E.M.; Gao, R.; White, M.C.; Uribe Roca, M.C.; Etcheverry, J.L.; Persi, G.; Poderoso, J.J.; Ashizawa, T. Ethnic origin and extrapyramidal signs in an Argentinean spinocerebellar ataxia type 10 family. Neurology 2007, 69, 216–218. [Google Scholar]
- Matsuura, T.; Achari, M.; Khajavi, M.; Bachinski, L.L.; Zoghbi, H.Y.; Ashizawa, T. Mapping of the gene for a novel spinocerebellar ataxia with pure cerebellar signs and epilepsy. Ann. Neurol. 1999, 45, 407–411. [Google Scholar] [CrossRef]
- Gallardo, M.; Soto, A. Clinical characterization of a Venezuelan family with spinocerebellar ataxia type 10. Mov. Disord. 2009, 24, S12. [Google Scholar]
- Teive, H.A.; Munhoz, R.P.; Raskin, S.; Arruda, W.O.; de Paola, L.; Werneck, L.C.; Ashizawa, T. Spinocerebellar ataxia type 10: Frequency of epilepsy in a large sample of Brazilian patients. Mov. Disord. 2010, 25, 2875–2878. [Google Scholar]
- van Zandvoort, M.A.; de Grauw, C.J.; Gerritsen, H.C.; Broers, J.L.; oude Egbrink, M.G.; Ramaekers, F.C.; Slaaf, D.W. Discrimination of DNA and RNA in cells by a vital fluorescent probe: Lifetime imaging of SYTO13 in healthy and apoptotic cells. Cytometry 2002, 47, 226–235. [Google Scholar] [CrossRef]
- Wakamiya, M.; Matsuura, T.; Liu, Y.; Schuster, G.C.; Gao, R.; Xu, W.; Sarkar, P.S.; Lin, X.; Ashizawa, T. The role of ataxin 10 in the pathogenesis of spinocerebellar ataxia type 10. Neurology 2006, 67, 607–613. [Google Scholar]
- Marz, P.; Probst, A.; Lang, S.; Schwager, M.; Rose-John, S.; Otten, U.; Ozbek, S. Ataxin-10, the spinocerebellar ataxia type 10 neurodegenerative disorder protein, is essential for survival of cerebellar neurons. J. Biol. Chem. 2004, 279, 35542–35550. [Google Scholar]
- Waragai, M.; Nagamitsu, S.; Xu, W.; Li, Y.J.; Lin, X.; Ashizawa, T. Ataxin 10 induces neuritogenesis via interaction with G-protein beta2 subunit. J. Neurosci. Res. 2006, 83, 1170–1178. [Google Scholar] [CrossRef]
- Andrali, S.S.; Marz, P.; Ozcan, S. Ataxin-10 interacts with O-GlcNAc transferase OGT in pancreatic beta cells. Biochem. Biophys. Res. Commun. 2005, 337, 149–153. [Google Scholar] [CrossRef]
- Stetefeld, J.; Bendfeldt, K.; Nitsch, C.; Reinstein, J.; Shoeman, R.L.; Dimitriades-Schmutz, B.; Schwager, M.; Leiser, D.; Ozcan, S.; et al. Ataxin-10 interacts with O-linked beta-N-acetylglucosamine transferase in the brain. J. Biol. Chem. 2006, 281, 20263–20270. [Google Scholar]
- Potaman, V.N.; Bissler, J.J.; Hashem, V.I.; Oussatcheva, E.A.; Lu, L.; Shlyakhtenko, L.S.; Lyubchenko, Y.L.; Matsuura, T.; Ashizawa, T.; Leffak, M. Unpaired structures in SCA10 (ATTCT)n.(AGAAT)n repeats. J. Mol. Biol. 2003, 326, 1095–1111. [Google Scholar] [CrossRef]
- Liu, G.; Bissler, J.J.; Sinden, R.R.; Leffak, M. Unstable spinocerebellar ataxia type 10 (ATTCT*(AGAAT) repeats are associated with aberrant replication at the ATX10 locus and replication origin-dependent expansion at an ectopic site in human cells. Mol. Cell. Biol. 2007, 27, 7828–7838. [Google Scholar] [CrossRef]
- Cherng, N.; Shishkin, A.A.; Schlager, L.I.; Tuck, R.H.; Sloan, L.; Matera, R.; Sarkar, P.S.; Ashizawa, T.; Freudenreich, C.H.; Mirkin, S.M. Expansions, contractions, and fragility of the spinocerebellar ataxia type 10 pentanucleotide repeat in yeast. Proc. Natl. Acad. Sci. USA 2011, 108, 2843–2848. [Google Scholar]
- Hagerman, K.A.; Ruan, H.; Edamura, K.N.; Matsuura, T.; Pearson, C.E.; Wang, Y.H. The ATTCT repeats of spinocerebellar ataxia type 10 display strong nucleosome assembly which is enhanced by repeat interruptions. Gene 2009, 434, 29–34. [Google Scholar] [CrossRef]
- Keren, B.; Jacquette, A.; Depienne, C.; Leite, P.; Durr, A.; Carpentier, W.; Benyahia, B.; Ponsot, G.; Soubrier, F.; Brice, A. Evidence against haploinsuffiency of human ataxin 10 as a cause of spinocerebellar ataxia type 10. Neurogenetics 2010, 11, 273–274. [Google Scholar] [CrossRef]
- White, M.C.; Gao, R.; Xu, W.; Mandal, S.M.; Lim, J.G.; Hazra, T.K.; Wakamiya, M.; Edwards, S.F.; Raskin, S.; Teive, H.A.G. Inactivation of hnRNP K by expanded intronic AUUCU repeat induces apoptosis via translocation of PKCdelta to mitochondria in spinocerebellar ataxia 10. PLoS Genet. 2010, 6, e1000984. [Google Scholar]
- White, M.; Xia, G.; Gao, R.; Wakamiya, M.; Sarkar, P.S.; McFarland, K.; Ashizawa, T. Transgenic mice with SCA10 pentanucleotide repeats show motor phenotype and susceptibility to seizure: A toxic RNA gain-of-function model. J. Neurosci. Res. 2012, 90, 706–714. [Google Scholar] [CrossRef]
- Handa, V.; Yeh, H.J.; McPhie, P.; Usdin, K. The AUUCU repeats responsible for spinocerebellar ataxia type 10 form unusual RNA hairpins. J. Biol. Chem. 2005, 280, 29340–29345. [Google Scholar]
- Borchelt, D.R.; Davis, J.; Fischer, M.; Lee, M.K.; Slunt, H.H.; Ratovitsky, T.; Regard, J.; Copeland, N.G.; Jenkins, N.A.; Sisodia, S.S. A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet. Anal. 1996, 13, 159–163. [Google Scholar] [CrossRef]
- Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 1999, 21, 70–71. [Google Scholar] [CrossRef]
- Schauwecker, P.E. The relevance of individual genetic background and its role in animal models of epilepsy. Epilepsy Res. 2011, 97, 1–11. [Google Scholar] [CrossRef]
- Ferraro, T.N.; Golden, G.T.; Smith, G.G.; Berrettini, W.H. Differential susceptibility to seizures induced by systemic kainic acid treatment in mature DBA/2J and C57BL/6J mice. Epilepsia 1995, 36, 301–307. [Google Scholar] [CrossRef]
- Schauwecker, P.E.; Steward, O. Genetic determinants of susceptibility to excitotoxic cell death: Implications for gene targeting approaches. Proc. Natl. Acad. Sci. USA 1997, 94, 4103–4108. [Google Scholar] [CrossRef]
- Forss-Petter, S.; Danielson, P.E.; Catsicas, S.; Battenberg, E.; Price, J.; Nerenberg, M.; Sutcliffe, J.G. Transgenic mice expressing beta-galactosidase in mature neurons under neuron-specific enolase promoter control. Neuron 1990, 5, 187–197. [Google Scholar] [CrossRef]
- Vandaele, S.; Nordquist, D.T.; Feddersen, R.M.; Tretjakoff, I.; Peterson, A.C.; Orr, H.T. Purkinje cell protein-2 regulatory regions and transgene expression in cerebellar compartments. Genes Dev. 1991, 5, 1136–1148. [Google Scholar] [CrossRef]
- Oberdick, J.; Smeyne, R.J.; Mann, J.R.; Zackson, S.; Morgan, J.I. A promoter that drives transgene expression in cerebellar Purkinje and retinal bipolar neurons. Science 1990, 248, 223–226. [Google Scholar]
- Saunders, T.L. Inducible transgenic mouse models. Methods Mol. Biol. 2011, 693, 103–115. [Google Scholar] [CrossRef]
- Furth, P.A.; St. Onge, L.; Boger, H.; Gruss, P.; Gossen, M.; Kistner, A.; Bujard, H.; Hennighausen, L. Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proc. Natl. Acad. Sci. USA 1994, 91, 9302–9306. [Google Scholar]
- Kistner, A.; Gossen, M.; Zimmermann, F.; Jerecic, J.; Ullmer, C.; Lubbert, H.; Bujard, H. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc. Natl. Acad. Sci. USA 1996, 93, 10933–10938. [Google Scholar]
- Moscardo, E.; Maurin, A.; Dorigatti, R.; Champeroux, P.; Richard, S. An optimised methodology for the neurobehavioural assessment in rodents. J. Pharmacol. Toxicol. Methods 2007, 56, 239–255. [Google Scholar] [CrossRef]
- Rogers, D.C.; Fisher, E.M.; Brown, S.D.; Peters, J.; Hunter, A.J.; Martin, J.E. Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm. Genome 1997, 8, 711–713. [Google Scholar] [CrossRef]
- Bailey, K.R.; Rustay, N.R.; Crawley, J.N. Behavioral phenotyping of transgenic and knockout mice: Practical concerns and potential pitfalls. ILAR J. 2006, 47, 124–131. [Google Scholar]
- Crawley, J.N. Behavioral phenotyping of transgenic and knockout mice: Experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res. 1999, 835, 18–26. [Google Scholar] [CrossRef]
- Crawley, J.N. Mouse behavioral assays relevant to the symptoms of autism. Brain Pathol. 2007, 17, 448–459. [Google Scholar] [CrossRef]
- Roullet, F.I.; Crawley, J.N. Mouse models of autism: Testing hypotheses about molecular mechanisms. Curr. Top. Behav. Neurosci. 2011, 7, 187–212. [Google Scholar] [CrossRef]
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McFarland, K.N.; Ashizawa, T. Transgenic Models of Spinocerebellar Ataxia Type 10: Modeling a Repeat Expansion Disorder. Genes 2012, 3, 481-491. https://doi.org/10.3390/genes3030481
McFarland KN, Ashizawa T. Transgenic Models of Spinocerebellar Ataxia Type 10: Modeling a Repeat Expansion Disorder. Genes. 2012; 3(3):481-491. https://doi.org/10.3390/genes3030481
Chicago/Turabian StyleMcFarland, Karen N., and Tetsuo Ashizawa. 2012. "Transgenic Models of Spinocerebellar Ataxia Type 10: Modeling a Repeat Expansion Disorder" Genes 3, no. 3: 481-491. https://doi.org/10.3390/genes3030481