Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues

Strong, Theresa V.; Tagle, Danilo A.; Valdes, John; Elmer, Lawrence; Boehm, Karina; Swaroop, Manju; Kaatz, Kevin W.; Collins, Francis S.; Albin, Roger L.

doi:10.1038/ng1193-259

Cited by 369 publications

(200 citation statements)

References 14 publications

Supporting

Mentioning

182

Contrasting

Unclassified

Order By: Relevance

“…The dramatic and selective loss of striatal tissue seen in HD, and the resultant pronounced behavioral and pathological effects, have remained unexplained (1,10,11). Given that the striatum is the predominant target of midbrain dopamine neurons, we sought to determine whether dopamine signaling might be altered in presymptomatic HD mice.…”

Section: H Untington's Disease (Hd) Is An Inherited Neurodegenerativementioning

confidence: 99%

Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice

Bibb

Yan

Svenningsson

et al. 2000

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

263

212

View full text Add to dashboard Cite

In Huntington's disease (HD), mutation of huntingtin causes selective neurodegeneration of dopaminoceptive striatal medium spiny neurons. Transgenic HD model mice that express a portion of the diseasecausing form of human huntingtin develop a behavioral phenotype that suggests dysfunction of dopaminergic neurotransmission. Here we show that presymtomatic mice have severe deficiencies in dopamine signaling in the striatum. These include selective reductions in total levels of dopamine-and cAMP-regulated phosphoprotein, Mr 32 kDA (DARPP-32) and other dopamine-regulated phosphoprotein markers of medium spiny neurons. HD mice also show defects in dopamine-regulated ion channels and in the D1 dopamine͞DARPP-32 signaling cascade. These presymptomatic defects may contribute to HD pathology. H untington's disease (HD) is an inherited neurodegenerative disorder characterized by progressive motor, psychiatric, and cognitive disturbances. The motor disturbance begins subtly, as minor adventitious movements, and gradually progresses until the entire body is consumed in flagrant chorea and uncontrolled writhing, leading to death 10-20 years after onset (1). HD pathology is characterized by specific neurodegeneration of the caudate nucleus and putamen (2, 3). Genetic analysis has established a causative link between HD and abnormal expansion of a polyglutamine repeat in the protein huntingtin (4). The transgenic mouse line R6͞2 (HD mice) is a well-characterized animal model of HD in which a fragment of a disease-causing variant of human huntingtin is ectopically expressed. These mice exhibit HD-like behavioral changes beginning after 8 weeks of life, progressively deteriorate over the succeeding 10 weeks, and die prematurely (5, 6). Although the HD mice are essentially asymptomatic until week 8, behavioral deficits are preceded by the appearance of intranuclear inclusion bodies in the central nervous system (7,8). These inclusions are similar to those detected in HD and other diseases associated with polyglutamine expansions (7-9).Both normal and mutant huntingtin are expressed throughout the body. The dramatic and selective loss of striatal tissue seen in HD, and the resultant pronounced behavioral and pathological effects, have remained unexplained (1, 10, 11). Given that the striatum is the predominant target of midbrain dopamine neurons, we sought to determine whether dopamine signaling might be altered in presymptomatic HD mice. We found that while many parameters of neuronal function remained unchanged, there were significant deficits including severely impaired electrophysiological and biochemical responses to activation of D1-class dopamine receptors, which precede the emergence of histopathological and behavioral changes. Materials and MethodsForskolin was purchased from LC Laboratories. 8-BromocAMP and protease type XIV were purchased from Sigma. SKF81297, D1 receptor antibodies, kainic acid, dopamine, and ␥-aminobutyric acid (GABA) were purchased from Research Biochemicals. Actin antibodies were purchased from BRL....

show abstract

Section: H Untington's Disease (Hd) Is An Inherited Neurodegenerativementioning

confidence: 99%

Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice

Bibb

Yan

Svenningsson

et al. 2000

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

263

212

View full text Add to dashboard Cite

show abstract

“…HD patients carry expanded glutamine repeats in the N terminus of huntingtin, a widely expressed protein of unknown function (2,3). Although huntingtin is expressed in many cell types, the primary cellular pathology of HD is degeneration of neurons of the striatum and cortex, leading to dramatic personality changes and motor dysfunction in early stages of the disease (4,5).…”

Section: A T Least Eight Hereditary Neurodegenerative Disorders Inclmentioning

confidence: 99%

Glutamine/proline-rich PQE-1 proteins protect Caenorhabditis elegans neurons from huntingtin polyglutamine neurotoxicity

Faber

Voisine

King

et al. 2002

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

113

View full text Add to dashboard Cite

Huntington's disease is a progressive neurodegenerative disease caused by a polyglutamine (polyQ) repeat expansion in the huntingtin protein [Huntington's Disease Collaborative Research Group (1993) Cell 72, 971-983]. To understand the mechanism by which polyQ repeats cause neurodegeneration and cell death, we modeled polyQ neurotoxicity in Caenorhabditis elegans. In our model, expression of N-terminal fragments of human huntingtin causes polyQdependent degeneration of neurons. We conducted a genetic screen to identify proteins that protect neurons from the toxic effects of expanded polyQ tracts. Loss of polyQ enhancer-1 (pqe-1) gene function strongly and specifically exacerbates neurodegeneration and cell death, whereas overexpression of a pqe-1 cDNA protects C. elegans neurons from the toxic effects of expanded huntingtin fragments. A glutamine͞proline-rich domain, along with a charged domain, is critical for PQE-1 protein function. Analysis of pqe-1 suggests that proteins exist that specifically protect neurons from the toxic effects of expanded polyQ disease proteins. A t least eight hereditary neurodegenerative disorders, includingHuntington's disease (HD), have been identified in which the disease locus encodes a protein containing an expanded glutamine tract (1). HD patients carry expanded glutamine repeats in the N terminus of huntingtin, a widely expressed protein of unknown function (2, 3). Although huntingtin is expressed in many cell types, the primary cellular pathology of HD is degeneration of neurons of the striatum and cortex, leading to dramatic personality changes and motor dysfunction in early stages of the disease (4, 5). Generally, the onset of disease symptoms is inversely related to the length of the glutamine expansion. However, additional factors distinct from polyglutamine (polyQ) length influence the age of onset. For example, genotypic variation linked to a region encoding the GluR6 kainate receptor accounts for Ϸ10% of the variance in the age of onset (6, 7).Molecular aspects of HD provide clues toward understanding the mechanism by which mutant huntingtin causes neurotoxicity. Expanded glutamine tracts in the huntingtin protein alter its physical properties (8, 9). PolyQ-containing N-terminal fragments of mutant huntingtin form cytosolic and nuclear aggregates in affected tissue (10). Therefore, the expanded glutamine tract in mutant huntingtin may elicit neurotoxicity by altering interactions of huntingtin with critical cellular constituents. For example, in the yeast two-hybrid system, normal huntingtin associates with Hip1, a human homolog of the yeast cytoskeletal protein, Sla2 (11-13). Loss of a normal interaction between Hip1 and mutant huntingtin may disrupt cytoskeletal integrity, leading to degeneration. Furthermore, transcription factors are sequestered by mutant huntingtin, interfering with normal gene transcription (14-16). Thus, the mechanisms of pathogenesis of HD may be triggered by changes or alterations of interactions with normal or abnormal protein partners.The mo...

show abstract

“…1 The causative mutation of HD is a dominantly heritable expansion of a trinucleotide CAG repeat in the coding region of the huntingtin gene, which results in long stretches of polyglutamine in the N-terminal portion of the huntingtin (htt) protein. 2 Although htt is ubiquitously expressed in the central nervous system, 3 its mutation induces a selective regional and temporal pattern of neurodegeneration. The more severe and early degeneration affects striatal projection neurons whereas loss of cortical neurons is observed at late stages of the disease.…”

mentioning

confidence: 99%

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

et al. 2009

View full text Add to dashboard Cite

Dysregulation of gene expression is one of the mechanisms involved in the pathophysiology of Huntington's disease (HD). Here, we examined whether mutant huntingtin regulates the levels of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1), a phosphatase that specifically dephosphorylates Akt at Ser473. Our results show decreased PHLPP1 protein levels in knock-in models (Hdh Q111/Q111 mouse striatum and STHdh Q111/Q111 cells), in the striatum of N-terminal exon-1 mutant huntingtin transgenic mouse models (R6/1; R6/1 : BDNF þ /À, R6/2 and Tet/HD94) and in the putamen of HD patients. Quantitative PCR analysis revealed a reduction in PHLPP1 mRNA levels in the striatum of R6/1 compared with wild-type mice. Coincident with reduced PHLPP1 protein levels, we observed increased phosphorylated Akt (Ser473) levels specifically in the striatum. The analysis of the conditional mouse model Tet/HD94 disclosed that after mutant huntingtin shutdown PHLPP1 levels returned to wild-type levels whereas phospho-Akt levels were partially reduced. In conclusion, our results show that mutant huntingtin downregulates PHLPP1 expression. In the striatum, these reduced levels of PHLPP1 can contribute to maintain high levels of activated Akt that may delay cell death and allow the recovery of neuronal viability after mutant huntingtin silencing.

show abstract

Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues

Cited by 369 publications

References 14 publications

Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice

Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice

Glutamine/proline-rich PQE-1 proteins protect Caenorhabditis elegans neurons from huntingtin polyglutamine neurotoxicity

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

Contact Info

Product

Resources

About