SCA1 transgenic mice: A model for neurodegeneration caused by an expanded CAG trinucleotide repeat

Burright, Eric N.; Clark, H. Brent; Servadio, Antonio; Matilla, T.; Feddersen, Richard M.; Yunis, Wael S.; Duvick, Lisa A.; Zoghbi, Huda Y.; Orr, Harry T.

doi:10.1016/0092-8674(95)90273-2

Cited by 559 publications

(475 citation statements)

References 30 publications

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“…We used the B05 model 2 for this work as the RNAi trigger expressed from rAAV1.miS1 targets human ATXN1. B05 transgenic mice show progressive disease, with transcriptional changes evident prior to noted behavioral deficits (Fig 1C).…”

Section: Resultsmentioning

confidence: 99%

“…Mice were genotyped using primers specific for the mutant human ataxin-1 transgene. 2 Hemizygous and age-matched wildtype littermates were used for the indicated experiments. Treatment groups comprised of approximately equal numbers of male and female mice.…”

Section: Methodsmentioning

confidence: 99%

“…2,3 This mouse, known as the B05 model, develops progressive disease, with many features similar to SCA1 including measurable gait deficits by 7 weeks of age. Additionally, there are transcriptional changes by postnatal day 25 and PC loss by 24 weeks of age.…”

Section: Introductionmentioning

confidence: 99%

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RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

Keiser

Monteys

Corbau

et al. 2016

Annals of Neurology

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Objective Spinocerebellar ataxia type 1 is an autosomal dominant fatal neurodegenerative disease caused by a polyglutamine expansion in the coding region of ATXN1. We showed previously that partial suppression of mutant ataxin-1 (ATXN1) expression, using virally-expressed RNAi triggers, could prevent disease symptoms in a transgenic mouse model and a knock in mouse model of the disease, using a single dose of virus. Here, we set out to test if RNAi triggers targeting ATXN1 could not only prevent, but also reverse disease readouts when delivered after symptom onset. Methods We administered recombinant adeno-associated virus (rAAV) expressing miS1, an artificial miRNA targeting human ATXN1 mRNA (rAAV.miS1) to a mouse model of SCA1 (B05 mice). Viruses were delivered prior to or after symptom onset at multiple doses. Control B05 mice were treated with rAAVs expressing a control artificial miRNA, or with saline. Animal behavior, molecular phenotypes, neuropathology and magnetic resonance spectroscopy were done on all groups and data were compared to wildtype littermates. Results We found that SCA1 phenotypes could be reversed by partial suppression of human mutant ATXN1 mRNA by rAAV.miS1 when delivered after symptom onset. We also identified the therapeutic range of rAAV.miS1 that could prevent or reverse disease readouts. Interpretation SCA1 disease may be reversible by RNAi therapy, and the doses required for advancing this therapy to humans are delineated.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

Keiser

Monteys

Corbau

et al. 2016

Annals of Neurology

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“…Homozygous ATXN1[82Q] transgenic mice,25 which overexpress human ATXN1 with 82 CAG repeats selectively in cerebellar Purkinje neurons under the Pcp2 promotor, were maintained on an FVB background. Wild‐type FVB mice (Jackson Labs) were used as controls for all experiments.…”

Section: Methodsmentioning

confidence: 99%

Targeting potassium channels to treat cerebellar ataxia

Bushart

Chopra

Singh

et al. 2018

Ann Clin Transl Neurol

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ObjectivePurkinje neuron dysfunction is associated with cerebellar ataxia. In a mouse model of spinocerebellar ataxia type 1 (SCA1), reduced potassium channel function contributes to altered membrane excitability resulting in impaired Purkinje neuron spiking. We sought to determine the relationship between altered membrane excitability and motor dysfunction in SCA1 mice.MethodsPatch‐clamp recordings in acute cerebellar slices and motor phenotype testing were used to identify pharmacologic agents which improve Purkinje neuron physiology and motor performance in SCA1 mice. Additionally, we retrospectively reviewed records of patients with SCA1 and other autosomal‐dominant SCAs with prominent Purkinje neuron involvement to determine whether currently approved potassium channel activators were tolerated.ResultsActivating calcium‐activated and subthreshold‐activated potassium channels improved Purkinje neuron spiking impairment in SCA1 mice (P < 0.05). Additionally, dendritic hyperexcitability was improved by activating subthreshold‐activated potassium channels but not calcium‐activated potassium channels (P < 0.01). Improving spiking and dendritic hyperexcitability through a combination of chlorzoxazone and baclofen produced sustained improvements in motor dysfunction in SCA1 mice (P < 0.01). Retrospective review of SCA patient records suggests that co‐treatment with chlorzoxazone and baclofen is tolerated.InterpretationTargeting both altered spiking and dendritic membrane excitability is associated with sustained improvements in motor performance in SCA1 mice, while targeting altered spiking alone produces only short‐term improvements in motor dysfunction. Potassium channel activators currently in clinical use are well tolerated and may provide benefit in SCA patients. Future clinical trials with potassium channel activators are warranted in cerebellar ataxia.

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“…Several animal models have been generated and investigated (Burright et al, 1995;Fernandez-Funez et al, 2000;Watase et al, 2002;Emamian et al, 2003;Chen et al, 2003) in order to understand the processes that underlie the onset and progression of SCA1. Data show that mutant ATAXIN1 protein levels have a key role in modulating disease pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

Giovannoni

Maggio²,

Bianco³

et al. 2007

Neuron Glia Biol.

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Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeats within the coding sequence of the ataxin-1 protein. In the present study, we used a conditional transgenic mouse model of SCA1 to investigate very early molecular and morphological changes related to the behavioral phenotype. In mice with neural deficits detected by rotarod performance, and simultaneous spatial impairments in exploratory activity and uncoordinated gait, we observed both significant altered expression and patchy distribution of excitatory amino acids transporter 1. The molecular changes observed in astroglial compartments correlate with changes in synapse morphology; synapses have a dramatic reduction of the synaptic area external to the postsynaptic density. By contrast, Purkinje cells demonstrate preserved structure. In addition, severe reactive astrocytosis matches changes in the glial glutamate transporter and synapse morphology. We propose these morpho-molecular changes are the cause of altered synaptic transmission, which, in turn, determines the onset of the neurological symptoms by altering the synaptic transmission in the cerebellar cortex of transgenic animals. This model might be suitable for testing drugs that target activated glial cells in order to reduce CNS inflammation.Keywords: EAAT1, synaptic plasticity, SCA1, neurodegeneration INTRODUCTIONThe contribution of non-neuronal cells to the pathogenesis of neurodegenerative diseases has been described although the mechanism remains poorly understood. The role of neuron-glia interactions is also being investigated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (Sheldon and Robinson, 2007). Moreover, glial dysfunction is likely to contribute to the pathogenesis of cerebellar ataxia in a mouse model of spinocerebellar ataxia type 7 (SCA7) (Custer et al., 2006).Excitatory amino acids transporter 1 (EAAT1, also known as GLAST) is the major glutamate transporter in the cerebellum (Lehre and Danbolt, 1998). It is expressed strongly by astrocytes in the molecular layer of the cerebellum and is at highest density on Bergmann glia. EAAT1 is not detected in neurons (Ginsberg et al., 1995). EAAT1 present on the plasma membrane of the astrocytic processes and cell bodies (Chaudhry et al., 1995). Targeting of EAAT1 is regulated carefully on astroglial membranes facing the neuropil, large dendrites, cell bodies and capillary endothelium (Danbolt, 2001). Therefore, its distribution follows the morphological changes of astrocytes during inflammatory processes. Recently, in a mouse model of reactive astrocytosis in the spinal cord, it has been reported that this glial process includes a marked proteolytic cascade having as substrates glial transporters. Subsequent changes in neurotransmitter uptake represent the basis of morphological and functional changes that sustain central plasticity . Moreover, glial activation involves changes in cell phenotype and gene expression that might trig...

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SCA1 transgenic mice: A model for neurodegeneration caused by an expanded CAG trinucleotide repeat

Cited by 559 publications

References 30 publications

RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

Targeting potassium channels to treat cerebellar ataxia

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

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