Ubiquitous expression of human SCA2 gene under the regulation of the SCA2 self promoter cause specific Purkinje cell degeneration in transgenic mice

Aguiar, Jorge; Fernández, Julio R.; Aguilar, A.; Mendoza, Yssel; Vázquez, María; Suárez, José; Berlanga, Jorge; Cruz, Silian; Guillén, Gerardo; Herrera, Luís; Velázquez, Luís; Santos, Nieves; Merino, Nelsón

doi:10.1016/j.neulet.2005.09.020

Cited by 40 publications

(23 citation statements)

References 19 publications

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“…12 It has been hypothesized that the abnormal excitatory activity responsible for post-hypoxic myoclonus is generated in the brainstem, 13 and Welsh et al postulated that loss of Purkinje cells in a concentrated region could remove the basal inhibition of deep cerebellar nuclei that project to the brainstem. 12 Although not as well documented in cardiac arrest studies, ataxia is strongly correlated with Purkinje cell loss in a number of clinical disorders, including spinocerebellar ataxia, alcoholic cerebellar degeneration, 33 Niemann-Pick disease type C1, 34 and paraneoplastic cerebellar degeneration 35 Additionally, selective Purkinje cell degeneration has been shown to cause ataxia in animal models of spinocerebellar ataxia, [36][37][38] Niemann-Pick disease type C1, 39 and chronic ethanol exposure. 40 Currently, a better understanding of the contribution of cerebellar injury on neurologic outcome after cardiac arrest is needed.…”

Section: Implications For Neurologic Outcomes After Cardiac Arrestmentioning

confidence: 99%

Cerebellar Purkinje cell neurodegeneration after cardiac arrest: Effect of therapeutic hypothermia

Paine

Che

et al. 2012

Resuscitation

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Section: Implications For Neurologic Outcomes After Cardiac Arrestmentioning

confidence: 99%

Cerebellar Purkinje cell neurodegeneration after cardiac arrest: Effect of therapeutic hypothermia

Paine

Che

et al. 2012

Resuscitation

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“…The following models will be discussed chronologically according to their publication year, consisting of 4 transgenic and 1 Knock-in (KI) mice: Q58 (Huynh et al, 2000); Q75 (Aguiar et al, 2006); Q42KI (Damrath et al, 2012); Q127 (Hansen et al, 2013); BAC-Q72 (Dansithong et al, 2015). …”

Section: Sca2 Mouse Modelsmentioning

confidence: 99%

“…Another model was developed in 2006, when Aguiar et al (2006) used the same methodology of pronuclear microinjection to create a mouse model with a human full-length version of ATXN2. The human gene was isolated from a Cuban patient with 75 CAG using RT-PCR and obtaining an amplicon of 4.477 Kb corresponding to the cDNA of the ataxin-2 isoform 1.…”

Section: Q75mentioning

confidence: 99%

Motor Dysfunctions and Neuropathology in Mouse Models of Spinocerebellar Ataxia Type 2: A Comprehensive Review

et al. 2016

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Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant ataxia caused by an expansion of CAG repeats in the exon 1 of the gene ATXN2, conferring a gain of toxic function that triggers the appearance of the disease phenotype. SCA2 is characterized by several symptoms including progressive gait ataxia and dysarthria, slow saccadic eye movements, sleep disturbances, cognitive impairments, and psychological dysfunctions such as insomnia and depression, among others. The available treatments rely on palliative care, which mitigate some of the major symptoms but ultimately fail to block the disease progression. This persistent lack of effective therapies led to the development of several models in yeast, C. elegans, D. melanogaster, and mice to serve as platforms for testing new therapeutic strategies and to accelerate the research on the complex disease mechanisms. In this work, we review 4 transgenic and 1 knock-in mouse that exhibit a SCA2-related phenotype and discuss their usefulness in addressing different scientific problems. The knock-in mice are extremely faithful to the human disease, with late onset of symptoms and physiological levels of mutant ataxin-2, while the other transgenic possess robust and well-characterized motor impairments and neuropathological features. Furthermore, a new BAC model of SCA2 shows promise to study the recently explored role of non-coding RNAs as a major pathogenic mechanism in this devastating disorder. Focusing on specific aspects of the behavior and neuropathology, as well as technical aspects, we provide a highly practical description and comparison of all the models with the purpose of creating a useful resource for SCA2 researchers worldwide.

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“…In 2006, a transgenic mouse line was generated in Cuba, expressing the full-length human SCA2 gene (named ATXN2) with 75 reiterations of CAG trinucleotide repeats under the control of the human SCA2 promoter. It was expected that this line would allow future studies on the benefits of therapeutic molecules and the underlying neuropathological mechanisms in this human disorder [15].…”

Section: Historical Background Of Sca2 Research In Cubamentioning

confidence: 99%

“…These animals became ataxic at 26 and 16 weeks in the heterozygous and homozygous transgenic mice, respectively, and displayed morphological alterations of Purkinje cells. In 2006, Aguiar and colleagues [15] generated transgenic mouse techniques demonstrated the specific degeneration of Purkinje neuron in the cerebellar cortex. The cell loss was associated with apoptosis as was demonstrated by the immunodetection of the activated form of caspase-3 and Bax protein overexpression.…”

Section: Animal Modelsmentioning

confidence: 99%

A Comprehensive Review of Spinocerebellar Ataxia Type 2 in Cuba

et al. 2011

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Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia characterized by a progressive cerebellar syndrome associated to saccadic slowing, peripheral neuropathy, cognitive disorders, and other multisystem features. SCA2 is caused by the abnormal expansion of cytosine-adenine-guanine triplet repeats in the encoding region of the ATXN2 gene and therefore the expression of toxic polyglutamine expansions in the ataxin 2 protein, which cause progressive neuronal death of Purkinje cells in the cerebellum and several pontine, mesencephalic, and thalamic neurons among other cells. Worldwide, SCA2 is the second most frequent type of spinocerebellar ataxia, only surpassed by SCA3. Nevertheless, in Holguin, Cuba, the disease reaches the highest prevalence, resulting from a putative foundational effect. This review discusses the most important advances in the genotypical and phenotypical studies of SCA2, highlighting the comprehensive characterization reached in Cuba through clinical, neuroepidemiological, neurochemical, and neurophysiological evaluation of SCA2 patients and presymptomatic subjects, which has allowed the identification of new disease biomarkers and therapeutical opportunities. These findings provide guidelines, from a Cuban viewpoint, for the clinical management of the disease, its diagnosis, genetic counseling, and therapeutical options through rehabilitative therapy and/or pharmacological options.

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Ubiquitous expression of human SCA2 gene under the regulation of the SCA2 self promoter cause specific Purkinje cell degeneration in transgenic mice

Cited by 40 publications

References 19 publications

Cerebellar Purkinje cell neurodegeneration after cardiac arrest: Effect of therapeutic hypothermia

Cerebellar Purkinje cell neurodegeneration after cardiac arrest: Effect of therapeutic hypothermia

Motor Dysfunctions and Neuropathology in Mouse Models of Spinocerebellar Ataxia Type 2: A Comprehensive Review

A Comprehensive Review of Spinocerebellar Ataxia Type 2 in Cuba

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