Mouse models of Huntington's disease

Menalled, Liliana; Chesselet, Marie‐Françoise

doi:10.1016/s0165-6147(00)01884-8

Cited by 266 publications

(170 citation statements)

References 86 publications

Supporting

Mentioning

162

Contrasting

Unclassified

Order By: Relevance

“…Most HD models use huntingtin genes with very long CAG repeats (>100) to induce a robust phenotype (5). To date, no assay in live cells has noted a phenotype at polyglutamine lengths close to 37 repeats or even typical HD repeat lengths.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Caron

Desmond

Xia

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

134

150

View full text Add to dashboard Cite

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion within the huntingtin gene that encodes a polymorphic glutamine tract at the amino terminus of the huntingtin protein. HD is one of nine polyglutamine expansion diseases. The clinical threshold of polyglutamine expansion for HD is near 37 repeats, but the mechanism of this pathogenic length is poorly understood. Using Förster resonance energy transfer, we describe an intramolecular proximity between the N17 domain and the downstream polyproline region that flanks the polyglutamine tract of huntingtin. Our data support the hypothesis that the polyglutamine tract can act as a flexible domain, allowing the flanking domains to come into close spatial proximity. This flexibility is impaired with expanded polyglutamine tracts, and we can detect changes in huntingtin conformation at the pathogenic threshold for HD. Altering the structure of N17, either via phosphomimicry or with small molecules, also affects the proximity between the flanking domains. The structural capacity of N17 to fold back toward distal regions within huntingtin requires an interacting protein, protein kinase C and casein kinase 2 substrate in neurons 1 (PACSIN1). This protein has the ability to bind both N17 and the polyproline region, stabilizing the interaction between these two domains. We also developed an antibody-based FRET assay that can detect conformational changes within endogenous huntingtin in wild-type versus HD fibroblasts. Therefore, we hypothesize that wild-type length polyglutamine tracts within huntingtin can form a flexible domain that is essential for proper functional intramolecular proximity, conformations, and dynamics.polyglutamine diseases | conformational switching | FLIM-FRET | neurodegeneration | fluorescence lifetime imaging microscopy H untington disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat within the huntingtin (HTT) gene (1). The pathogenic threshold of CAG expansion is ∼37 repeats, with increased repeats leading to an earlier age-onset of HD (2-4). This CAG mutation results in an expanded polyglutamine tract in the amino terminus of the gene's protein product, huntingtin (1). To date, no phenotypes at the level of huntingtin molecular biology or animal models can be attributed to polyglutamine lengths near the human pathogenic disease threshold (5).Polyglutamine or glutamine-rich domains are also found in transcription factors such as the Sp-family and cAMP response element-binding protein (CREB) and are defined as proteinprotein interaction motifs used to scaffold and regulate transcription by RNA polymerase II (6, 7). In the transducin-like enhancer of split (TLE) corepressor proteins, the glutamine-rich domains are thought to allow dimerization (8). However, the role of polyglutamine in proteins such as huntingtin may be distinct from that of a protein-protein interaction or dimerization domain.The polyglutamine tract of huntingtin is flanked on...

show abstract

Section: Resultsmentioning

confidence: 99%

“…This CAG mutation results in an expanded polyglutamine tract in the amino terminus of the gene's protein product, huntingtin (1). To date, no phenotypes at the level of huntingtin molecular biology or animal models can be attributed to polyglutamine lengths near the human pathogenic disease threshold (5).…”

mentioning

confidence: 99%

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Caron

Desmond

Xia

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

134

150

View full text Add to dashboard Cite

show abstract

“…It is also likely that the full extent of the learning impairments observed here cannot solely be correlated with corticostriatal dysfunction, as hippocampal plasticity or other central and peripheral physiologies have also been shown to be changed in several lines of transgenic mice (19,20), including R6/1 line. However, as the type of procedural learning studied here has been known to require an intact striatum (21), pathologies of other brain areas including the hippocampus are not likely to be primarily associated with the severe learning deficits observed in R6/1 mice.…”

Section: Discussionmentioning

confidence: 98%

Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease

Cayzac

Delcasso

Paz

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

In hereditary neurodegenerative Huntington disease (HD), early cognitive impairments before motor deficits have been hypothesized to result from dysfunction in the striatum and cortex before degeneration. To test this hypothesis, we examined the firing properties of single cells and local field activity in the striatum and cortex of pre-motor-symptomatic R6/1 transgenic mice while they were engaged in a procedural learning task, the performance on which typically depends on the integrity of striatum and basal ganglia. Here, we report that a dramatically diminished recruitment of the vulnerable striatal projection cells, but not local interneurons, of R6/1 mice in coding for the task, compared with WT littermates, is associated with severe deficits in procedural learning. In addition, both the striatum and cortex in these mice showed a unique oscillation at high γ-frequency. These data provide crucial information on the in vivo cellular processes in the corticostriatal pathway through which the HD mutation exerts its effects on cognitive abilities in early HD.single unit | local field potential | high γ-oscillation | operant learning | pre-motor-symptomatic R6/1 mice H untington disease (HD) is a progressive and inherited neurodegenerative disorder associated with selective degeneration of medium-sized spiny projection neurons in the striatum (1). Although the disease is well characterized by symptoms such as involuntary choreiform movements, dystonias, and rigidity, these motor symptoms have been found to be preceded by personality, mood, and cognitive disturbances (2). Some postmortem studies have also shown only limited signs of pathologic processes or cell loss in the brain despite substantial clinical evidence of HD (3), suggesting that neuronal-and, more precisely, synapticdysfunction, rather than cell death, may predominantly underlie early behavioral manifestations of the HD mutation.Studies of the effects of the mutant HD gene in several transgenic mouse models, including the R6 lines, have indeed shown changes in the membrane properties, biochemistry, and morphology of fragile striatal cells (4, 5), suggesting compromised functional integrity. They have also shown early and progressive alterations in synaptic plasticity in the corticostriatal pathway (6). These changes have been hypothesized to underlie early cognitive and behavioral deficits in transgenic mice (and patients with HD) by altering striatal information processing and transfer within basal ganglia loops.To verify this hypothesis, we recorded single-unit activity and local field potentials (LFPs) in the dorsal striatum and cortex, whereas behaviorally naive pre-motor-symptomatic R6/1 mice (7) (14-18 wk old) and age-matched WT littermates acquired an association between a nose-poke (NP) action and reward through operant learning. This procedural learning of an action-reward association is known to critically involve the striatum, a crucial site for the integration of the sensorimotor, limbic, and cognitive information required for the selecti...

show abstract

“…Chez la drosophile, la huntingtine ne contient ni domaines polyglutamines ni régions riches en proline. Des progrès notables dans la compréhension des mécanismes de la maladie de Huntington ont été réalisés grâce au développement de modèles biochimiques, cellulaires, génétiques et lésionnels [21][22][23]. En particulier, les phénotypes d'inactivation du gène codant pour la huntingtine chez la souris suggèrent que la protéine serait impliquée dans la neurogenèse [19] et dans la survie neuronale à l'âge adulte [20].…”

Section: La Chorée De Huntington Physiopathologieunclassified

C. elegans comme modèle pour les maladies dégénératives héréditaires humaines

Ségalat

Néri²

2003

Med Sci (Paris)

View full text Add to dashboard Cite

Mouse models of Huntington's disease

Cited by 266 publications

References 86 publications

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease

C. elegans comme modèle pour les maladies dégénératives héréditaires humaines

Contact Info

Product

Resources

About