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• W133070834 abstract "Huntington’s disease (HD) is a devastating, genetic, neurodegenerative disease for which there is currently no effective therapy. The polyglutamine (polyQ) expansion that causes HD is in the first exon (HDx1) of huntingtin (Htt). However, other parts of the protein, including the 17 N-terminal amino acids (AAs) and two proline (polyP) repeat domains, modulate the toxicity of mutant Htt (mHtt). The role of the P-rich domain that is flanked by the polyP domains has not been explored. Using highly specific intracellular antibodies (intrabodies; iAbs), we tested various epitopes for their roles in mHDx1 toxicity, aggregation, localization and turnover. Three domains in the P-rich region (PRR) of HDx1 are defined by iAbs: MW7 binds the two polyP domains, and Happs 1 and 3, two new iAbs, bind the unique, P-rich epitope located between the two polyP epitopes. In cultured cells, we find that the three PRR-binding iAbs, as well as VL12.3, which binds an epitope in the N-terminal 17 AA segment, decrease the toxicity and aggregation of mHDx-1, but they do so by different mechanisms. The PRR-binding iAbs have no effect on Htt localization, but they cause a significant increase in the turnover rate of mHtt, which VL12.3 does not change. In contrast, expression of VL12.3 increases nuclear Htt. These results suggest that the PRR domain regulates mHtt stability and toxicity. Thus, compromising this pathogenic epitope by iAb binding represents a novel therapeutic strategy for treating HD. We have tested this hypothesis by delivering both VL12.3 and Happ1 to the brains of HD model mice using an AAV2/1 viral vector with a modified CBA promoter. VL12.3 treatment, while beneficial in a lentiviral model of HD, has no effect on the YAC128 HD model and actually increases severity of phenotype and mortality in the R6/2 HD model. In contrast, Happ1 treatment confers significant beneficial effects in assays of motor and cognitive deficits as well as in the neuropathology found in the lentiviral, R6/2, N171-82Q, YAC128 and BACH models of HD. These results indicate that increasing the turnover of mHtt using AAV-Happ1 gene therapy represents a highly specific and effective treatment possibility for HD." @default.
• W133070834 created "2016-06-24" @default.
• W133070834 creator A5071902829 @default.
• W133070834 date "2009-01-01" @default.
• W133070834 modified "2023-09-24" @default.
• W133070834 title "Intrabodies as Therapeutics for Huntington's Disease" @default.
• W133070834 cites W1481077857 @default.
• W133070834 cites W1498027344 @default.
• W133070834 cites W1529494566 @default.
• W133070834 cites W1550227666 @default.
• W133070834 cites W157684288 @default.
• W133070834 cites W1606431180 @default.
• W133070834 cites W1643390591 @default.
• W133070834 cites W1661834421 @default.
• W133070834 cites W1750171938 @default.
• W133070834 cites W1844768017 @default.
• W133070834 cites W1949056714 @default.
• W133070834 cites W1964203623 @default.
• W133070834 cites W1964433270 @default.
• W133070834 cites W1966037459 @default.
• W133070834 cites W1966815691 @default.
• W133070834 cites W1968573900 @default.
• W133070834 cites W1969483326 @default.
• W133070834 cites W1970456057 @default.
• W133070834 cites W1970458326 @default.
• W133070834 cites W1970549330 @default.
• W133070834 cites W1972747973 @default.
• W133070834 cites W1974750355 @default.
• W133070834 cites W1975005653 @default.
• W133070834 cites W1975583867 @default.
• W133070834 cites W1975932182 @default.
• W133070834 cites W1977265431 @default.
• W133070834 cites W1977383752 @default.
• W133070834 cites W1977569817 @default.
• W133070834 cites W1977983193 @default.
• W133070834 cites W1978181170 @default.
• W133070834 cites W1978611833 @default.
• W133070834 cites W1981326800 @default.
• W133070834 cites W1988142389 @default.
• W133070834 cites W1988859034 @default.
• W133070834 cites W1989386072 @default.
• W133070834 cites W1989619236 @default.
• W133070834 cites W1990665436 @default.
• W133070834 cites W1992305831 @default.
• W133070834 cites W1993575340 @default.
• W133070834 cites W1993861337 @default.
• W133070834 cites W1995321160 @default.
• W133070834 cites W1996353639 @default.
• W133070834 cites W1996592124 @default.
• W133070834 cites W1997883336 @default.
• W133070834 cites W1998383469 @default.
• W133070834 cites W2000446177 @default.
• W133070834 cites W2000725549 @default.
• W133070834 cites W2001086078 @default.
• W133070834 cites W2002654912 @default.
• W133070834 cites W2003715450 @default.
• W133070834 cites W2004054097 @default.
• W133070834 cites W2004817863 @default.
• W133070834 cites W2006155616 @default.
• W133070834 cites W2006179777 @default.
• W133070834 cites W2006351633 @default.
• W133070834 cites W2008724789 @default.
• W133070834 cites W2009401980 @default.
• W133070834 cites W2009761723 @default.
• W133070834 cites W2009979848 @default.
• W133070834 cites W2012481532 @default.
• W133070834 cites W2016390889 @default.
• W133070834 cites W2017689311 @default.
• W133070834 cites W2020340826 @default.
• W133070834 cites W2021976516 @default.
• W133070834 cites W2022976505 @default.
• W133070834 cites W2024032885 @default.
• W133070834 cites W2024612758 @default.
• W133070834 cites W2025438498 @default.
• W133070834 cites W2027450659 @default.
• W133070834 cites W2029732186 @default.
• W133070834 cites W2030667534 @default.
• W133070834 cites W2030845517 @default.
• W133070834 cites W2033643225 @default.
• W133070834 cites W2035550470 @default.
• W133070834 cites W2041907686 @default.
• W133070834 cites W2042498352 @default.
• W133070834 cites W2042739691 @default.
• W133070834 cites W2047638794 @default.
• W133070834 cites W2047885160 @default.
• W133070834 cites W2049947935 @default.
• W133070834 cites W2050276749 @default.
• W133070834 cites W2052883021 @default.
• W133070834 cites W2052935486 @default.
• W133070834 cites W2054037688 @default.
• W133070834 cites W2058470791 @default.
• W133070834 cites W2060100216 @default.
• W133070834 cites W2060601033 @default.
• W133070834 cites W2061921105 @default.
• W133070834 cites W2062535497 @default.
• W133070834 cites W2062682951 @default.
• W133070834 cites W2063471759 @default.
• W133070834 cites W2063865625 @default.
• W133070834 cites W2063997730 @default.
• W133070834 cites W2064791021 @default.

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