Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation

Davies, Stephen; Turmaine, Mark; Cozens, Barbara A.; DiFiglia, Marian; Sharp, Alan H.; Ross, Christopher A.; Scherzinger, Eberhard; Wanker, Erich E.; Mangiarini, Laura; Bates, Gillian P.

doi:10.1016/s0092-8674(00)80513-9

Cited by 2,047 publications

(1,586 citation statements)

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“…Thus the polyQ-length-dependent aggregation of HTTex1 in vitro mirrors observations in patients and in transgenic model systems [8,9].…”

Section: Pathogenic Polyq-containing Protein Aggregates In Patients Asupporting

confidence: 52%

“…These aggregates, which are often concentrated in large inclusion bodies, are observed in brain regions that display massive neurodegeneration, suggesting that the process of polyQ-mediated protein misfolding and aggregation drives pathogenesis [8]. This hypothesis is supported by investigations in transgenic mouse, fly and worm models, which indicate that toxicity in neuronal cells correlates with the formation of polyQcontaining protein aggregates [9]. Moreover, in vitro studies with polyQ disease proteins have demonstrated that both spontaneous protein aggregation and toxicity are dependent on polyQ length.…”

Section: Introductionmentioning

confidence: 88%

“…The deposition of N-terminal HTT protein fragments with expanded polyQ sequences in neuronal inclusion bodies (IBs) is one pathological characteristic of HD brains [8,9]. IBs, which generally have a diameter of 1-5 µm, are predominantly detected in cortical and striatal neurons [12;45].…”

Section: Pathogenic Polyq-containing Protein Aggregates In Patients Amentioning

confidence: 99%

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Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

Trepte

Strempel

Wanker

2014

Essays in Biochemistry

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Published in final edited form as:Trepte, P., Strempel, N., Wanker, E.E. Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures. Abstract:Polyglutamine ( This chapter reviews the current literature regarding misfolding and aggregation of polyQ-containing disease proteins. We specifically focus on studies that have investigated the amyloidogenesis of polyQ-containing huntingtin exon 1 (HTTex1) fragments. These protein fragments are disease-relevant and play a critical role in HD pathogenesis. We will outline potential mechanisms behind mutant HTTex1 aggregation and toxicity, as well as proteins and small molecules that can modify HTTex1 amyloidogenesis in vitro and in vivo. The potential implications of such studies for the development of novel therapeutic strategies are discussed.

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“…Thus the polyQ-length-dependent aggregation of HTTex1 in vitro mirrors observations in patients and in transgenic model systems [8,9].…”

Section: Pathogenic Polyq-containing Protein Aggregates In Patients Asupporting

confidence: 52%

Section: Introductionmentioning

confidence: 88%

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Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

Trepte

Strempel

Wanker

2014

Essays in Biochemistry

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“…Although mtHtt lacks a nuclear localization signal, mtHtt can translocate to the nucleus and produce neurotoxicity in cell culture models. [101][102][103][104] Reportedly, the mtHtt/SNO-GAPDH/Siah1 complex translocates to the nucleus, enabling mtHtt to contribute to toxicity. 100 Supporting Figure 4 Possible mechanism of S-nitrosylated GAPDH (SNO-GAPDH) contributing to neuronal cell damage or death.…”

Section: S-nitrosylation As a Potential Positive Regulator Of Excitotmentioning

confidence: 99%

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Nakamura

Lipton

2007

Cell Death Differ

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Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca 2 þ influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones -such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins -can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

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“…Characteristic neuropathological findings in SCA1 are the loss of Purkinje cells in the cerebellum and neurons in the inferior olivary complex (Robitaille et al, 1995). As described for other polyglutamine diseases such as Huntingdon's disease (HD) Davies et al, 1997), the presence of neuronal intranuclear inclusions (NIs) in Purkinje cells in human patients and in a transgenic mouse model (Skinner et al, 1997) represents a pathological hallmark of SCA 1. Recent evidence shows that compounds that increase inclusion formation might reduce cellular pathology in several neurodegenerative disorders (Bodner et al, 2006).…”

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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Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation

Cited by 2,047 publications

References 47 publications

Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

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

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