TY  - JOUR
AU  - Stahl, Fabian
AU  - Evert, Bernd O.
AU  - Han, Xinyu
AU  - Breuer, Peter
AU  - Wüllner, Ullrich
TI  - Spinocerebellar Ataxia Type 3 Pathophysiology—Implications for Translational Research and Clinical Studies
JO  - International journal of molecular sciences
VL  - 25
IS  - 7
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - DZNE-2024-00359
SP  - 3984
PY  - 2024
AB  -  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.
KW  - Humans
KW  - Animals
KW  - Machado-Joseph Disease: genetics
KW  - Translational Research, Biomedical
KW  - Spinocerebellar Ataxias: genetics
KW  - Translational Science, Biomedical
KW  - Animals, Genetically Modified
KW  - ASO (Other)
KW  - CRISPR/Cas (Other)
KW  - SREBP (Other)
KW  - cholesterol (Other)
KW  - clinical trials (Other)
KW  - compound modifier (Other)
KW  - genomic modifier (Other)
KW  - high throughput screening (Other)
KW  - miRNA (Other)
KW  - spinocerebellar ataxia 3 (SCA3) (Other)
KW  - transcriptional and posttranscriptional regulation (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:38612794
C2  - pmc:PMC11012515
DO  - DOI:10.3390/ijms25073984
UR  - https://pub.dzne.de/record/268860
ER  -