Identification and characterization of the gene causing type 1 spinocerebellar ataxia

Banfi, Sandro; Servadio, Antonio; Chung, Ming Yi; Kwiatkowski, Thomas J.; McCall, Alanna E.; Duvick, Lisa A.; Shen, Ying H.; Roth, E. Jill; Orr, Harry T.; Zoghbi, Huda Y.

doi:10.1038/ng0894-513

Cited by 329 publications

(185 citation statements)

References 31 publications

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“…SCA1 belongs to the polyglutamine disorders, a group of inherited neurodegenerative diseases caused by expansion of a translated CAG repeat in the coding region of the SCA1 gene (Schols et al, 2004;Orr and Zoghbi, 2007). The characterization of SCA1 (Banfi et al, 1994) allowed ataxin-1 (ATAXIN1) the protein it encodes, to be identified as the molecule responsible for disease pathogenesis and progression. ATAXIN1 is expressed in the CNS throughout life, localized mainly in the nucleus, both in its normal and mutated configuration, with some cytoplasmic localization in cerebellar Purkinje cells .…”

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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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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“…SCA1 is caused by the inheritance of a single copy of ataxin-1 with a polyglutamine-encoding region that ranges from 44 to 82 CAG repeats. 29 Expression of mutant ataxin-1 leads to ataxia that progressively worsens over time, loss of Purkinje cells and brainstem neurons and cerebellar atrophy. Mutant ataxin-1, like the amino terminus of mutant huntingtin, translocates to the nucleus where it forms inclusion bodies.…”

Section: Dominantly Inherited Neurologic Diseases Induced By Nucleotimentioning

confidence: 99%

RNAi: a potential therapy for the dominantly inherited nucleotide repeat diseases

Denovan‐Wright

Davidson

2005

Gene Ther

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“…In contrast, the length of expanded CAG repeat in the SCA1 disease chromosomes ranges from 39 up to 81 repeats. The length of expansion is inversely correlated with age-of-onset of disease, suggesting a direct role of CAG repeat/polyglutamine length in the pathogenesis of SCA1 Orr et al 1993;Banfi et al 1994).…”

Section: Introductionmentioning

confidence: 98%

“…Spinocerebellar ataxia type 1 (SCA1) (OMIM: #164400) is caused by an expansion of trinucleotide (CAG) repeat that encodes polyglutamine tract in the ataxin-1 (ATXN1) gene (OMIM: *601556) lying in the short arm of human chromosome 6 (6p23) Orr et al 1993;Banfi et al 1994). In normal chromosomes, this CAG repeat shows repeat-length polymorphism ranging in size between 19 and 39 repeats.…”

Section: Introductionmentioning

confidence: 99%

Direct and accurate measurement of CAG repeat configuration in the ataxin-1 (ATXN-1) gene by “dual-fluorescence labeled PCR-restriction fragment length analysis”

et al. 2008

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Identification and characterization of the gene causing type 1 spinocerebellar ataxia

Cited by 329 publications

References 31 publications

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

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

RNAi: a potential therapy for the dominantly inherited nucleotide repeat diseases

Direct and accurate measurement of CAG repeat configuration in the ataxin-1 (ATXN-1) gene by “dual-fluorescence labeled PCR-restriction fragment length analysis”

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