Identification of genes that modify ataxin-1-induced neurodegeneration

Fernández-Fúnez, Pedro; Niño-Rosales, María Laura; Gouyon, Béatrice; She, Wei Chi; Luchak, James M.; Martı́nez, Pedro; Turiégano, Enrique; Benito, Jonathan; Capovilla, Maria; Skinner, Pamela J.; McCall, Alanna E.; Canal, Inmaculada; Orr, Harry T.; Zoghbi, Huda Y.; Botas, Juan

doi:10.1038/35040584

Cited by 629 publications

(539 citation statements)

References 21 publications

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“…The present results suggest that histidines interrupting the polyQ stretch of ataxin-1 suppress the misfolding of the expanded polyQ specifically recognized by the 1C2 MoAb. This finding is consistent with the hypothesis formulated by Fernandez-Funez et al [4] upon the observation that also normal ataxin-1 is toxic if expressed in excess. According to this hypothesis, ataxin-1 has more than one stable conformation, and even a low percentage of the normal protein misfolds towards a pathogenic conformation.…”

Section: Discussionsupporting

confidence: 93%

Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro

Calabresi

Guida

Servadio³

et al. 2001

Brain Research Bulletin

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Spinocerebellar ataxia type 1 is a neurodegenerative disease caused by expansion of an uninterrupted glutamine repeat in ataxin-1 protein. Protein aggregation and immunoreactivity to 1C2 monoclonal antibody are two distinct pathognomonic features of expanded ataxin-1, as well as of other polyglutamine disorders. Rare cases of non-affected elderly subjects carrying expanded ataxin-1 alleles were found in random population. However, in these alleles the glutamine stretch was interrupted by histidines. Due to lack of phenotype, these alleles should be considered "normal". Most importantly, occurrence of these unusual alleles provides a unique opportunity to investigate which molecular properties of expanded ataxin-1 are not coupled to polyglutamine pathogenesis. Towards this goal, we compared in vitro the immunoreactivity to 1C2 antibody and the ability to form aggregates of interrupted and uninterrupted alleles. Immunoblotting showed that expandedinterrupted ataxin-1 had an affinity to 1C2 resembling that of normal ataxin-1. On the contrary, filter assay showed that aggregation rate of expanded-interrupted ataxin-1 resembles that of expanded-uninterrupted ataxin-1. These observations indicate that affinity for 1C2 does not directly correlate with selfaggregation of ataxin-1. Moreover, self-aggregation is not directly affected by histidine interruptions. In conclusion, these results support the hypothesis that mechanisms underlying neuronal degeneration are triggered by protein misfolding rather than by protein aggregation. © 2001 Elsevier Science Inc.KEY WORDS: Spinocerebellar ataxia type 1, SCA1, Trinucleotide expansion, Amyloid-like protein aggregates.

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Section: Discussionsupporting

confidence: 93%

Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro

Calabresi

Guida

Servadio³

et al. 2001

Brain Research Bulletin

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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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“…neurons in the larval ventral nerve cord [ 21 ] , viability/eclosion rate ( see Note 1 ), motor function by using the climbing assay, survival/longevity assay, etc.…”

Section: Crossing Schemes To Analyze Neurodegeneration In Htt Challenmentioning

confidence: 99%

“…In fl ies with very little pigment, the rhabdomeres can be impossible to see by this technique; thus, it is better to use a driver that has a strong mini w + or cross a wild-type w + gene into your w − transgenic fl ies. If pigmented eyes are not possible, another measure of retinal degeneration is to fi x and section the eye and measure the retinal thickness [ 21 ] .…”

Section: Count the Rhabdomeresmentioning

confidence: 99%

Morphometric Analysis of Huntington’s Disease Neurodegeneration in Drosophila

Song

Smith

Syed

et al. 2013

Methods in Molecular Biology

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Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The HD gene encodes the huntingtin protein (HTT) that contains polyglutamine tracts of variable length. Expansions of the CAG repeat near the amino terminus to encode 40 or more glutamines (polyQ) lead to disease. At least eight other expanded polyQ diseases have been described [1]. HD can be faithfully modeled in Drosophila with the key features of the disease such as late onset, slowly progressing degeneration, formation of abnormal protein aggregates and the dependence on polyQ length being evident. Such invertebrate model organisms provide powerful platforms to explore neurodegenerative mechanisms and to productively speed the identi fi cation of targets and agents that are likely to be effective at treating diseases in humans. Here we describe an optical pseudopupil method that can be readily quanti fi ed to provide a fast and sensitive assay for assessing the degree of HD neurodegeneration in vivo . We discuss detailed crossing schemes as well as factors including different drivers, various constructs, the number of UAS sites, genetic background, and temperature that can in fl uence the result of pseudopupil measurements.

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Identification of genes that modify ataxin-1-induced neurodegeneration

Cited by 629 publications

References 21 publications

Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro

Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro

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

Morphometric Analysis of Huntington’s Disease Neurodegeneration in Drosophila

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