Molecular clues unveiling spinocerebellar ataxia type-12 pathogenesis

Manish Kumar; Shweta Sahni; Vivekanand A; Deepak Kumar; Neetu Kushwah; Divya Goel; Himanshi Kapoor; Achal K Srivastava; Mohammed Faruq

doi:10.1016/j.isci.2024.109768

Molecular clues unveiling spinocerebellar ataxia type-12 pathogenesis

iScience. 2024 Apr 18;27(5):109768. doi: 10.1016/j.isci.2024.109768. eCollection 2024 May 17.

Authors

Manish Kumar^{1

2

3}, Shweta Sahni^{1

4}, Vivekanand A^{1

2

3}, Deepak Kumar^{5

6}, Neetu Kushwah¹, Divya Goel⁷, Himanshi Kapoor¹, Achal K Srivastava⁴, Mohammed Faruq^{1

2

3}

Affiliations

¹ Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology (CSIR -IGIB), Mall Road, Delhi 110007, India.
² CSIR-HRDC Campus, Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
³ Genomics and Molecular Medicine Division, CSIR - Institute of Genomics and Integrative Biology, New Delhi, India.
⁴ Department of Neurology, All India Institute of Medical Sciences, New Delhi 110029, India.
⁵ Division of Genomics and Molecular Medicine, CSIR - Institute of Genomics and Integrative Biology (IGIB), New Delhi 110007, India.
⁶ Department of Zoology, University of Allahabad, Prayagraj, Uttar Pradesh 211002, India.
⁷ Department of Pharmacology, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi 110062, India.

Abstract

Spinocerebellar Ataxia type-12 (SCA12) is a neurodegenerative disease caused by tandem CAG repeat expansion in the 5'-UTR/non-coding region of PPP2R2B. Molecular pathology of SCA12 has not been studied in the context of CAG repeats, and no appropriate models exist. We found in human SCA12-iPSC-derived neuronal lineage that expanded CAG in PPP2R2B transcript forms nuclear RNA foci and were found to sequester variety of proteins. Further, the ectopic expression of transcript containing varying length of CAG repeats exhibits non-canonical repeat-associated non-AUG (RAN) translation in multiple frames in HEK293T cells, which was further validated in patient-derived neural stem cells using specific antibodies. mRNA sequencing of the SCA12 and control neurons have shown a network of crucial transcription factors affecting neural fate, in addition to alteration of various signaling pathways involved in neurodevelopment. Altogether, this study identifies the molecular signatures of SCA12 disorder using patient-derived neuronal cell lines.

Keywords: Molecular biology; Neuroscience.