Loss of normal huntingtin function: new developments in Huntington's disease research

Cattaneo, Elena; Rigamonti, Dorotea; Goffredo, Donato; Zuccato, Chiara; Squitieri, Ferdinando; Sipione, Simonetta

doi:10.1016/s0166-2236(00)01721-5

Cited by 335 publications

(208 citation statements)

References 78 publications

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“…Neuronal death in HD has been variously attributed to polyQ toxicity, activation of caspases, interference with transcriptional machinery, and sequestration͞inactivation of wild-type htt and other important cellular factors (12)(13)(14)(15)(16)(17). Several proteins that interact with exon 1 of htt have been identified (14,(18)(19)(20)(21)(22)(23), and although the function of these proteins in the etiology of HD is unclear, the transcriptional coactivator CREB-binding protein (CBP) as well as proteins with WW domains have been implicated in the HD pathology (18)(19)(20)(21).…”

mentioning

confidence: 99%

Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity

Khoshnan

Ko²,

Patterson³

2002

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

140

114

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We have generated eight mAbs (MW1-8) that bind the epitopes polyglutamine (polyQ), polyproline (polyP), or the C terminus of exon 1 in huntingtin (htt) protein. In the brains of Huntington's disease (HD) mouse models, the anti-polyQ mAbs bind to various cytoplasmic compartments, whereas the anti-polyP and anti-C terminus mAbs bind nuclear inclusions containing htt. To use these mAbs as intracellular perturbation agents, we have cloned and expressed the antigen-binding domains of three of the mAbs as single-chain variable region fragment Abs (scFvs). In 293 cells cotransfected with htt exon 1 containing an expanded polyQ domain, MW1, MW2, and MW7 scFvs colocalize with htt exon 1. Moreover, these scFvs coimmunoprecipitate with htt exon 1 in cell extracts. In perturbation experiments, MW7 scFv, recognizing the polyP domains of htt, significantly inhibits aggregation as well as the cell death induced by mutant htt protein. In contrast, MW1 and MW2 scFvs, recognizing the polyQ stretch, stimulate htt aggregation and apoptosis. Therefore, these anti-htt scFvs can be used to investigate the role of the polyP and polyQ domains in HD pathogenesis, and antibody binding to the polyP domain has potential therapeutic value in HD. H untington's disease (HD), a fatal neurodegenerative disorder, is caused by abnormal expansion of CAG repeats that translate into an extended polyglutamine (polyQ) stretch in exon 1 of the protein huntingtin (htt) (1). Mutant htt with Ͼ40 CAG repeats gains a toxic function and induces death in subpopulations of neurons in the striatum and cortex (2-4). A hallmark of HD and other polyQ diseases is the formation of insoluble protein aggregates in affected neurons (5, 6). A major component of the aggregates in HD is the N terminus exon 1 of mutant htt (2,(5)(6)(7)(8). Abnormal behavior and aggregate formation are also seen in transgenic mice expressing htt exon 1 with an expanded polyQ stretch (9-11).Neuronal death in HD has been variously attributed to polyQ toxicity, activation of caspases, interference with transcriptional machinery, and sequestration͞inactivation of wild-type htt and other important cellular factors (12-17). Several proteins that interact with exon 1 of htt have been identified (14,(18)(19)(20)(21)(22)(23), and although the function of these proteins in the etiology of HD is unclear, the transcriptional coactivator CREB-binding protein (CBP) as well as proteins with WW domains have been implicated in the HD pathology (18-21). Binding of htt to CBP has been shown to repress CBP-mediated gene expression (18,19). Moreover, ectopic expression of CBP appears to block httmediated toxicity, indicating that transcriptional dysregulation may contribute to HD pathogenesis (19,24). Several different WW-containing proteins have been shown to interact with proline-rich domains in the C terminus of htt exon 1 (20, 21). These interactors include spliceosomes (HYPA and HYPC) and transcription factors (HYPB), which appear to have a higher affinity for expanded polyQ htt (20). By using specific anti...

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mentioning

confidence: 99%

Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity

Khoshnan

Ko²,

Patterson³

2002

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

140

114

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“…Furthermore, experiments in the human neuroblastoma SH-SY5Y cell line have been central in unveiling DJ-1 protective activity against neuronal apoptosis. Therefore, the combined 'loss-and gain-of-functions' hypothesis would represent a provocative example for mechanisms of neurodegeneration, as already proven for Huntington's disease 36 and amyotrophic lateral sclerosis. 37 Materials and Methods Constructs.…”

Section: Discussionmentioning

confidence: 93%

Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson's disease-associated DJ-1 missense mutations

et al. 2008

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Mutations in PARK7 DJ-1 have been associated with autosomal-recessive early-onset Parkinson's disease (PD). This gene encodes for an atypical peroxiredoxin-like peroxidase that may act as a regulator of transcription and a redox-dependent chaperone. Although large gene deletions have been associated with a loss-of-function phenotype, the pathogenic mechanism of several missense mutations is less clear. By performing a yeast two-hybrid screening from a human fetal brain library, we identified TRAF and TNF receptor-associated protein (TTRAP), an ubiquitin-binding domain-containing protein, as a novel DJ-1 interactor, which was able to bind the PD-associated mutations M26I and L166P more strongly than wild type. TTRAP protected neuroblastoma cells from apoptosis induced by proteasome impairment. In these conditions, endogenous TTRAP relocalized to a detergent-insoluble fraction and formed cytoplasmic aggresome-like structures. Interestingly, both DJ-1 mutants blocked the TTRAP protective activity unmasking a c-jun N-terminal kinase (JNK)-and p38-MAPK (mitogen-activated protein kinase)-mediated apoptosis. These results suggest an active role of DJ-1 missense mutants in the control of cell death and position TTRAP as a new player in the arena of neurodegeneration. Cell Death and Differentiation (2009) Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder, affecting 1-2% of all individuals above the age of 65 years. Its neuropathological hallmark is the selective degeneration of subsets of mesencephalic dopaminergic cells and the formation of proteinaceous cytoplasmic aggregates called Lewy bodies. 1 Several studies implicate the ubiquitin-proteasome system in PD pathogenesis. 2 Synthetic proteasome inhibitors preferentially affect catecholaminergic neurons, leading to cell death. Furthermore, key ubiquitin-proteasome system elements are altered in PD post-mortem brains. [3][4][5] The identification of genes (PARK1-14) associated with familial PD has provided crucial insights into the pathogenic mechanisms. 1 The ubiquitin ligase parkin (PARK2) and the ubiquitin C-terminal hydrolase-L1 (UCH-L1) (PARK5) have been implicated in the ubiquitin-proteasome system function. Interestingly, upon treatment with proteasome inhibitors, they formed insoluble aggregates and were recruited to a juxtanuclear aggresome-like inclusion that resembled the Lewy body. 6,7 Autosomal-recessive early-onset PD has been associated with mutations in PARK7/DJ-1. 8 Functional DJ-1 is a dimer that acts as an atypical peroxiredoxin-like peroxidase as well as a regulator of transcription and a chaperone. 9-12 Interestingly, ectopic DJ-1 expression protects cells from death induced by a variety of insults. 13 DJ-1 loss in humans causes PD. 14 DJ-1 knock-out (KO) mice and flies showed increased vulnerabilities to neurotoxic agents but no signs of dopaminergic cell death. [15][16][17] PD families may also present missense mutations of DJ-1 in homozygous (L166P, M26I and E64D) and heterozygous forms (A104T and D149A)....

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“…In contrast, HD may be induced by a somewhat different mechanism because the disruption of Huntingtin is sufficient to induce neurodegeneration (Dragatsis et al, 2000). Thus it has been proposed that sequestering of wild-type Huntingtin proteins may contribute to the development of HD (Dragatsis et al, 2000;Cattaneo et al, 2001). In addition, the transgenic mouse models for HD and DRPLA manifest distinct behavioral and neuropathological phenotypes, despite the use of the same prion protein promoter (Schilling et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…However, different diseases may develop through different mechanisms. (Dragatsis et al, 2000;Cattaneo et al, 2001). In contrast, studies with SCA7 mutant mice suggested wild-type SCA7 proteins are not involved in pathogenesis (Yoo et al, 2003).…”

Section: Introductionmentioning

confidence: 96%

C‐terminal deletion of the atrophin‐1 protein results in growth retardation but not neurodegeneration in mice

Ying

Zhuang

et al. 2009

Developmental Dynamics

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Dentatorubral-pallidoluysian atrophy (DRPLA) is a dominant hereditary neurodegenerative disorder caused by the expansion of a poly-glutamine (poly-Q) repeat in Atrophin-1 protein. Ectopic expression of a poly-Q expanded human Atrophin-1 is sufficient to induce DRPLA phenotypes in mice. However, it is still unclear whether the dominant effect of poly-Q expansion is due to the functional interference with wildtype Atrophin-1 proteins, which exist in both patients and transgenic mice. Here we report the generation and analysis of an Atrophin-1 targeting allele that expresses a truncated protein lacking both the poly-Q repeat and following C-terminal peptides. Homozygous mutants exhibit growth retardation and progressive male infertility, but no obvious signs of neurodegeneration. Moreover, the mutant allele neither blocked nor enhanced the neurodegenerative phenotypes caused by a poly-Q expanded transgene. These results support the model that poly-Q expanded Atrophin-1 proteins cause DRPLA in a manner independent of any functional interaction with wild-type Atrophin-1 proteins.

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Loss of normal huntingtin function: new developments in Huntington's disease research

Cited by 335 publications

References 78 publications

Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity

Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity

Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson's disease-associated DJ-1 missense mutations

C‐terminal deletion of the atrophin‐1 protein results in growth retardation but not neurodegeneration in mice

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