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@ARTICLE{Stahl:268860,
      author       = {Stahl, Fabian and Evert, Bernd O. and Han, Xinyu and
                      Breuer, Peter and Wüllner, Ullrich},
      title        = {{S}pinocerebellar {A}taxia {T}ype 3
                      {P}athophysiology—{I}mplications for {T}ranslational
                      {R}esearch and {C}linical {S}tudies},
      journal      = {International journal of molecular sciences},
      volume       = {25},
      number       = {7},
      issn         = {1422-0067},
      address      = {Basel},
      publisher    = {Molecular Diversity Preservation International},
      reportid     = {DZNE-2024-00359},
      pages        = {3984},
      year         = {2024},
      abstract     = {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.},
      subtyp        = {Review Article},
      keywords     = {Humans / Animals / Machado-Joseph Disease: genetics /
                      Translational Research, Biomedical / Spinocerebellar
                      Ataxias: genetics / Translational Science, Biomedical /
                      Animals, Genetically Modified / ASO (Other) / CRISPR/Cas
                      (Other) / SREBP (Other) / cholesterol (Other) / clinical
                      trials (Other) / compound modifier (Other) / genomic
                      modifier (Other) / high throughput screening (Other) / miRNA
                      (Other) / spinocerebellar ataxia 3 (SCA3) (Other) /
                      transcriptional and posttranscriptional regulation (Other)},
      cin          = {AG Wüllner},
      ddc          = {540},
      cid          = {I:(DE-2719)1011302},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38612794},
      pmc          = {pmc:PMC11012515},
      doi          = {10.3390/ijms25073984},
      url          = {https://pub.dzne.de/record/268860},
}