Sp1 Is Up-regulated in Cellular and Transgenic Models of Huntington Disease, and Its Reduction Is Neuroprotective

Qiu, Zhihua; Norflus, Fran; Singh, Bhupinder; Swindell, Mary K.; Buzescu, Rodica; Bejarano, Michelle; Chopra, Raman; Zucker, Birgit; Benn, Caroline; DiRocco, Derek P.; Jang-Ho, J.; Ferrante, Robert J.; Hersch, Steven M.

doi:10.1074/jbc.m511648200

Cited by 100 publications

(84 citation statements)

References 46 publications

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“…that the transcription factor Sp1 drives the expression of p75 NTR upon neuronal injury or distinct stress inducers (32,33). Moreover, Sp1 has been described to be increased in cellular and transgenic models of HD (34). In accordance with these findings, we found a significant increase in Sp1 protein levels in the hippocampus of HD mice and HD human brain, supporting the idea that deregulation of Sp1 activity by mutant huntingtin could underlie the increase in p75 NTR mRNA observed in HD hippocampus.…”

Section: Discussionsupporting

confidence: 80%

“…We next aimed to determine the molecular mechanism by which mutant huntingtin induces aberrant hippocampal p75 NTR expression. The transcription factor Sp1 has been described to drive expression of p75 NTR under cellular stress conditions (32,33), while upregulation of Sp1 has been described in cellular and mouse models of HD (34). These data prompted us to investigate whether increased p75 NTR expression was related to higher hippocampal Sp1 levels.…”

Section: Increased P75mentioning

confidence: 99%

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Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

Brito¹,

Giralt²,

et al. 2014

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Section: Discussionsupporting

confidence: 80%

Section: Increased P75mentioning

confidence: 99%

Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

Brito¹,

Giralt²,

et al. 2014

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“…Because only soluble mutant htt binds Sp1, shorter htt fragments may bind Sp1 and prevent Sp1 binding to promoter DNA before they form aggregates. It should be noted that Sp1 mediates the expression of a large number of genes and is reported to be up-regulated in some models of HD (13,41). It is known that Sp1 expression is induced by oxidative stress in neurons (42).…”

Section: Discussionmentioning

confidence: 99%

Context-dependent Dysregulation of Transcription by Mutant Huntingtin

Cornett

Smith

Friedman

et al. 2006

Journal of Biological Chemistry

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Huntington disease (HD) is an adult-onset neurodegenerative disease caused by expansion of a polyglutamine (poly(Q) tract in the N-terminal region of huntingtin (htt). Although the precise mechanisms leading to neurodegeneration in HD have not been fully elucidated, transcriptional dysregulation has been implicated in disease pathogenesis. In HD, multiple N-terminal mutant htt fragments smaller than the first 500 amino acids have been found to accumulate in the nucleus and adversely affect gene transcription. It is unknown whether different htt fragments in the nucleus can differentially bind transcription factors and affect transcription. Here, we report that shorter N-terminal htt fragments, which are more prone to misfolding and aggregation, are more competent to bind Sp1 and inhibit its activity. These effects can be reversed by Hsp40, a molecular chaperone that reduces the misfolding of mutant htt. Our results provide insight into the beneficial effects of molecular chaperones and suggest that context dependent transcriptional dysregulation may contribute to differential toxicity of various N-terminal htt fragments. Huntington disease (HD)3 is an autosomal dominant neurodegenerative disorder resulting from expansion (Ͼ37 repeats) of a polyglutamine (poly(Q)) repeat in the N-terminal region of huntingtin (htt), a 350-kDa protein of unknown function. Proteolytic cleavage of full-length htt, which is predominantly cytoplasmic, generates N-terminal htt fragments that accumulate abnormally and form inclusions over time in neuronal nuclei (1). The nucleus is thought to be a primary site of poly(Q) toxicity, as blocking the nuclear entry of htt suppresses its ability to cause cell death (2), whereas targeting htt to the nucleus by the addition of a nuclear localization signal (NLS) causes a more severe phenotype (3-5).In the nucleus, mutant htt abnormally interacts with a number of transcription factors (6). Accordingly, the nuclear pathology observed in HD is thought to be largely due to transcriptional dysregulation (7,8). In fact, mRNA levels are altered for specific genes in HD mouse and cell models as well as in post-mortem human HD brain (7-11). Mutant htt has a higher affinity than normal htt for certain transcription factors, such as Sp1 (12-15), and these aberrant interactions can functionally deactivate transcription factors by titrating them away from their normal DNA binding sites (12)(13)(14)(15)(16).Biochemical analysis of HD knock-in mice that express a 150-glutamine repeat in the endogenous mouse htt (17) revealed the presence of multiple N-terminal htt fragments smaller than the first 508 amino acids in the nucleus (18), consistent with the notion that cleavage of mutant htt is a key event in HD pathology (19,20). Because htt protein length can influence its cellular toxicity and ability to cause neurodegeneration in HD cellular models and transgenic mice (21, 22), it is important to know whether nuclear N-terminal htt fragments of different length can differentially affect gene transcription. Und...

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“…Assuming these data correlate with the integrity of the nigrostriatal system, they could account for the less severe motor phenotype of the D9-N171-98Q mouse compared with the prp-N171-82Q model [25]. Our underlying assumption is that the changes noted in the D9-N171-98Q mouse striatum are cell autonomous, but can simultaneously be compensating for cell-intrinsic abnormalities [119,120]. The converse is also true (i.e., compensatory pathways may serve to normalize primary transcriptional alterations).…”

Section: Transcriptional Dysregulationmentioning

confidence: 99%

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Ehrlich

2012

Neurotherapeutics

120

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Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is >40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum. characterized by selective, or perhaps better described as differential [2], vulnerability with degeneration and death of the medium spiny neuron (MSN). The Gamma-aminobutyric acid (GABA)ergic MSN represents 95% of striatal neurons. They are all output neurons, with extensive intra-striatal connections with other MSNs and striatal interneurons. For the last two decades, increased attention has been paid to the pathology in the cortex (particularly in layers V and VI [3]), which contains the corticostriatal projection neurons.Prior to identification of the HTT gene, the huntingtin protein, and the nature of its mutation, it was assumed that selective neuronal vulnerability in HD would be conferred by the expression pattern of the mutated protein (polyQ-htt). As it is now apparent, htt is expressed throughout the nervous system and periphery, without a preference for, or higher level in, MSNs or cortical projection neurons [4].In the absence of enriched expression of a mutated protein, neuronal subtype vulnerability was assumed to arise from unique protein interactions. For example, in the study of another polyQ disease, spinocerebellar ataxia 7, the interaction between ataxin-7 and the homeobox protein CRX in the retina was reported to specifically lead to pathology [5]. In a followup study, the specific role of CRX was not confirmed [6]. To complicate matters further, the same group recently demonstrated that the interactions between a mutant polyQ protein, Ataxin-1, and 14-3-3epsilon differentially affects disease state in cerebellum and brainstem, both of which are vulnerable regions [7]. The regional distribution of the described huntingtin interacting proteins by and large does not explain MSN vulnerability [8][9][10]. One exception is the htt interacting protein RASD2/Rhes (Ras homologue enriched in striatum), which is striatal-specific. It is a small G-protein that mediates sumoylation of polyQ-htt, and thereby its neurotoxicity.

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Sp1 Is Up-regulated in Cellular and Transgenic Models of Huntington Disease, and Its Reduction Is Neuroprotective

Cited by 100 publications

References 46 publications

Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

Context-dependent Dysregulation of Transcription by Mutant Huntingtin

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

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