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000268860 1001_ $$0P:(DE-2719)2812610$$aStahl, Fabian$$b0$$eFirst author$$udzne
000268860 245__ $$aSpinocerebellar Ataxia Type 3 Pathophysiology—Implications for Translational Research and Clinical Studies
000268860 260__ $$aBasel$$bMolecular Diversity Preservation International$$c2024
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000268860 520__ $$a The spinocerebellar ataxias (SCA) comprise a group of inherited neurodegenerative diseases. Machado-Joseph Disease (MJD) or spinocerebellar ataxia 3 (SCA3) is the most common autosomal dominant form, caused by the expansion of CAG repeats within the ataxin-3 (ATXN3) gene. This mutation results in the expression of an abnormal protein containing long polyglutamine (polyQ) stretches that confers a toxic gain of function and leads to misfolding and aggregation of ATXN3 in neurons. As a result of the neurodegenerative process, SCA3 patients are severely disabled and die prematurely. Several screening approaches, e.g., druggable genome-wide and drug library screenings have been performed, focussing on the reduction in stably overexpressed ATXN3(polyQ) protein and improvement in the resultant toxicity. Transgenic overexpression models of toxic ATXN3, however, missed potential modulators of endogenous ATXN3 regulation. In another approach to identify modifiers of endogenous ATXN3 expression using a CRISPR/Cas9-modified SK-N-SH wild-type cell line with a GFP-T2A-luciferase (LUC) cassette under the control of the endogenous ATXN3 promotor, four statins were identified as potential activators of expression. We here provide an overview of the high throughput screening approaches yet performed to find compounds or genomic modifiers of ATXN3(polyQ) toxicity in different SCA3 model organisms and cell lines to ameliorate and halt SCA3 progression in patients. Furthermore, the putative role of cholesterol in neurodegenerative diseases (NDDs) in general and SCA3 in particular is discussed.
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000268860 650_2 $$2MeSH$$aHumans
000268860 650_2 $$2MeSH$$aAnimals
000268860 650_2 $$2MeSH$$aMachado-Joseph Disease: genetics
000268860 650_2 $$2MeSH$$aTranslational Research, Biomedical
000268860 650_2 $$2MeSH$$aSpinocerebellar Ataxias: genetics
000268860 650_2 $$2MeSH$$aTranslational Science, Biomedical
000268860 650_2 $$2MeSH$$aAnimals, Genetically Modified
000268860 650_7 $$2Other$$aASO
000268860 650_7 $$2Other$$aCRISPR/Cas
000268860 650_7 $$2Other$$aSREBP
000268860 650_7 $$2Other$$acholesterol
000268860 650_7 $$2Other$$aclinical trials
000268860 650_7 $$2Other$$acompound modifier
000268860 650_7 $$2Other$$agenomic modifier
000268860 650_7 $$2Other$$ahigh throughput screening
000268860 650_7 $$2Other$$amiRNA
000268860 650_7 $$2Other$$aspinocerebellar ataxia 3 (SCA3)
000268860 650_7 $$2Other$$atranscriptional and posttranscriptional regulation
000268860 7001_ $$aEvert, Bernd O.$$b1
000268860 7001_ $$aHan, Xinyu$$b2
000268860 7001_ $$0P:(DE-2719)9002874$$aBreuer, Peter$$b3$$udzne
000268860 7001_ $$0P:(DE-2719)2000056$$aWüllner, Ullrich$$b4$$eLast author
000268860 770__ $$aCNS Drug Action in Neurodegenerative Diseases 3.0
000268860 773__ $$0PERI:(DE-600)2019364-6$$a10.3390/ijms25073984$$gVol. 25, no. 7, p. 3984 -$$n7$$p3984$$tInternational journal of molecular sciences$$v25$$x1422-0067$$y2024
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