CRISPR/Cas9-Targeted Deletion of Polyglutamine in Spinocerebellar Ataxia Type 3-Derived Induced Pluripotent Stem Cells.

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  • Additional Information
    • Source:
      Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 101197107 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-8534 (Electronic) Linking ISSN: 15473287 NLM ISO Abbreviation: Stem Cells Dev Subsets: MEDLINE
    • Publication Information:
      Original Publication: Larchmont, NY : Mary Ann Liebert, Inc., c2004-
    • Subject Terms:
      CRISPR-Cas Systems* ; Gene Deletion*; Ataxin-3/*genetics ; Induced Pluripotent Stem Cells/*metabolism ; Machado-Joseph Disease/*genetics ; Peptides/*genetics ; Repressor Proteins/*genetics; Adult ; Cell Differentiation/genetics ; Cells, Cultured ; Female ; Gene Editing/methods ; Humans ; Induced Pluripotent Stem Cells/cytology ; Machado-Joseph Disease/metabolism ; Machado-Joseph Disease/pathology ; Neural Stem Cells/cytology ; Neural Stem Cells/metabolism ; Trinucleotide Repeat Expansion/genetics
    • Abstract:
      Spinocerebellar ataxia type 3 (SCA3) is caused by an abnormal expansion of the cytosine-adenine-guanine (CAG) triplet in ATXN3, which translates into a polyglutamine (polyQ) tract within ataxin-3 (ATXN3) protein. Although the pathogenic mechanisms remain unclear, it is well established that expression of mutant forms of ATXN3 carrying an expanded polyQ domain are involved in SCA3 pathogenesis, and several strategies to suppress mutant ATXN3 have shown promising potential for SCA3 treatment. In this study, we described successful clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated deletion of the expanded polyQ-encoding region of ATXN3 in induced pluripotent stem cells (iPSCs) derived from a SCA3 patient, and these patient-specific iPSCs retained pluripotency and neural differentiation following expanded polyQ deletion. Furthermore, the ubiquitin-binding capacity of ATXN3 was retained in the neural cells differentiated from the corrected iPSCs. For the first time, this work provides preliminary data for gene editing by CRISPR/Cas9 in SCA3, and demonstrates the feasibility of using a single-guide RNA pair to delete the expanded polyQ-encoding region of ATXN3, suggesting the potential efficacy of this method for future therapeutic application.
    • Contributed Indexing:
      Keywords: CRISPR/Cas9*; SCA3*; gene editing*; induced pluripotent cells*; polyglutamine*
    • Accession Number:
      0 (Peptides)
      0 (Repressor Proteins)
      26700-71-0 (polyglutamine)
      EC 3.4.19.12 (ATXN3 protein, human)
      EC 3.4.19.12 (Ataxin-3)
    • Publication Date:
      Date Created: 20180418 Date Completed: 20190924 Latest Revision: 20190925
    • Publication Date:
      20220301
    • Accession Number:
      10.1089/scd.2017.0209
    • Accession Number:
      29661116