Pathological Cell-Cell Interactions Elicited by a Neuropathogenic Form of Mutant Huntingtin Contribute to Cortical Pathogenesis in HD Mice

Gu, Xiaofeng; Li, Chenjian; Wei, Weizheng; Lo, Vincent; Gong, Shiaoching; Li, Shihua; Iwasato, Takuji; Itohara, Shigeyoshi; Li, Shengbo Eben; Módy, István; Heintz, Nathaniel; Yang, Xiangdong

doi:10.1016/j.neuron.2005.03.025

Cited by 211 publications

(221 citation statements)

References 68 publications

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“…Later studies have found that in a neuron-glia co-culture system, wild-type glial cells protect neurons against neurotoxicity caused by mutant Htt, whereas glial cells expressing mutant Htt increased neuronal vulnerability [2] . These studies indicate that cell-cell interactions between neurons and glial cells play an important role in HD pathology [3,4] . In addition, mutant Htt expressed in glial cells could exacerbate neurological symptoms in HD transgenic mice, so the role of glial cells in HD neuropathology should not be neglected [5] .…”

Section: Introductionmentioning

confidence: 80%

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes

Chen

Wang

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the effects of rapamycin on glutamate uptake in cultured rat astrocytes expressing N-terminal 552 residues of mutant huntingtin (Htt-552). Methods: Primary astrocyte cultures were prepared from the cortex of postnatal rat pups. An astrocytes model of Huntington's disease was established using the astrocytes infected with adenovirus carrying coden gene of N-terminal 552 residues of Huntingtin. The protein levels of glutamate transporters GLT-1 and GLAST, the autophagic marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and the autophagy substrate p62 in the astrocytes were examined using Western blotting. The mRNA expression levels of GLT-1 and GLAST in the astrocytes were determined using Real-time PCR. [ 3 H]glutamate uptake by the astrocytes was measured with liquid scintillation counting. Results: The expression of mutant Htt-552 in the astrocytes significantly decreased both the mRNA and protein levels of GLT-1 but not those of GLAST. Furthermore, Htt-552 significantly reduced [ 3 H]glutamate uptake by the astrocytes. Treatment with the autophagy inhibitor 3-MA (10 mmol/L) significantly increased the accumulation of mutant Htt-552, and reduced the expression of GLT-1 and [ 3 H]glutamate uptake in the astrocytes. Treatment with the autophagy stimulator rapamycin (0.2 mg/mL) significantly reduced the accumulation of mutant Htt-552, and reversed the changes in GLT-1 expression and [ 3 H]glutamate uptake in the astrocytes. Conclusion: Rapamcin, an autophagy stimulator, can prevent the suppression of GLT-1 expression and glutamate uptake by mutant Htt-552 in cultured astrocytes.

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Section: Introductionmentioning

confidence: 80%

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes

Chen

Wang

et al. 2012

Acta Pharmacol Sin

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“…Even more remarkably, we show that Igfbp5 down-regulation takes place through a non-cell-autonomous mechanism. Previous work supporting the importance of intercellular interactions in polyglutamine disorders has relied on the use of a truncated fragment of huntingtin or the overexpression of the mutant ATXN7 protein in cells that provide support to PCs (25)(26)(27). To date, however, this issue has not been investigated in KI models, whereby the mutant protein is expressed in the endogenous manner such that intercellular interactions and their influence on selective vulnerability can be investigated in the endogenous disease context.…”

Section: Discussion Common Transcriptional Changes Occur In Early-symmentioning

confidence: 99%

The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7

Gatchel¹,

Watase

Thaller³

et al. 2008

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

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Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG repeats encoding a glutamine tract in the disease-causing proteins. There are nine disorders, each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with degeneration of Purkinje cells. To determine whether the disorders share molecular pathogenic events, we studied two mouse models of SCA1 and SCA7 that express the glutamine-expanded protein from the respective endogenous loci. We found common transcriptional changes, with down-regulation of insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust changes. Igfbp5 down-regulation occurred in granule neurons through a non-cellautonomous mechanism and was concomitant with activation of the insulin-like growth factor (IGF) pathway and the type I IGF receptor on Purkinje cells. These data define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular mechanisms in their pathogenesis.cerebellum ͉ neurodegeneration ͉ polyglutamine ͉ Purkinje cell ͉ granule neuron P olyglutamine diseases are a group of inherited neurodegenerative disorders that include spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17 as well as Huntington disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA). They are caused by expansion of CAG repeats encoding a polyglutamine tract in different proteins (1). Evidence suggests that the polyglutamine expansion confers toxicity predominantly through a gain-of-function mechanism, although loss of function may also play a role (1, 2). Despite widespread expression of the disease proteins in the central nervous system (CNS), there is selective vulnerability of specific neurons in each disease (1). Such selective neuronal vulnerability gives rise to the specific features of each disease.SCA1 and SCA7 have distinct features while also sharing some key similarities. In SCA1, primary symptoms include ataxia, dysarthria, and bulbar dysfunction, whereas cognitive impairment is more varied (1). This presentation is associated with cerebellar atrophy and loss of Purkinje cells (PCs) and secondary loss of granule neurons (1). In SCA7, progressive visual loss, cerebellar ataxia, and dysarthria are the most common clinical features (3). In addition to retinal degeneration, cerebellar PCs and neurons of the dentate nucleus and inferior olive are among the earliest to degenerate (3).Given that SCA1 and SCA7 share a cerebellar degenerative phenotype, we proposed that some shared molecular changes might occur in both diseases, and that common molecular alterations could pinpoint pathways that could be targeted to modulate or monitor the pathogenesis of more than one disease. We focused on transcriptional changes because both ATXN1 and ATXN7 play roles in transcriptional regulation (4-8), and transcriptional defects can be detected in e...

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“…Pathological cell-cell interactions involving cortical inhibitory interneurons and pyramidal neurons have also been shown in transgenic mice expressing a pathogenic huntingtin mutant (mhtt-exon1) (Gu et al, 2005). In these mice, the ability of mhtt-exon1 to cause pyramidal cell degeneration depends on its expression in cortical GABAergic interneurons followed by the reduced generation of spontaneous inhibitory postsynaptic currents, a physiological marker of interneuron inhibition, in pyramidal neurons.…”

Section: Discussionmentioning

confidence: 99%

NMDA inhibitors cause apoptosis of pyramidal neurons in mature piriform cortex: Evidence for a nitric oxide-mediated effect involving inhibitory interneurons

et al. 2007

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Pyramidal relay neurons in limbic cortex are vulnerable to denervation lesions, i.e. pyramidal neurons in layer IIα of piriform cortex undergo transsynaptic apoptosis after lesions that interrupt their inputs from the olfactory bulb. We have previously established the role of inhibitory interneurons in elaborating signals that lead to the apoptosis of projection neurons in these lesion models, i.e. the upregulation of neuronal NOS and release of nitric oxide. Thus, we have proposed that cortical interneurons play an essential role in transducing injury to degenerative effects for nearby pyramidal neurons. In the present study, we extend the previous findings to a toxic model of degeneration of pyramidal neurons in the adult paralimbic cortex, i.e. after exposure to the NMDA channel blocker MK801. Our findings indicate that treatment of adult rats with MK801 in doses previously found to cause alterations in pyramidal neurons of the retrosplenial cortex (5 mg/kg) results in an active caspase 3 (+), ultrastructurally apoptotic type of cell death involving the same projection neurons of layer IIα that are also vulnerable to bulbotomy lesions. Interneurons of layer I are induced by MK801 treatment to higher levels of nNOS expression and the selective nNOS inhibitor BRNI ameliorates pyramidal cell apoptosis caused by MK801. Our results indicate that certain pyramidal neurons in piriform cortex are very sensitive to NMDA blockade as they are to disconnection from modalityspecific afferents and that inhibitory interneurons play significant roles in mediating various types of pro-apoptotic insults to cortical projection neurons via nNOS/NO signaling.

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Pathological Cell-Cell Interactions Elicited by a Neuropathogenic Form of Mutant Huntingtin Contribute to Cortical Pathogenesis in HD Mice

Cited by 211 publications

References 68 publications

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes

The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7

NMDA inhibitors cause apoptosis of pyramidal neurons in mature piriform cortex: Evidence for a nitric oxide-mediated effect involving inhibitory interneurons

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