Aberrant splicing in Huntington's disease accompanies disrupted TDP-43 activity and altered m6A RNA modification

Thai B Nguyen; Ricardo Miramontes; Carlos Chillon-Marinas; Roy Maimon; Sonia Vazquez-Sanchez; Alice L Lau; Nicolette R McClure; Zhuoxing Wu; Keona Q Wang; Whitney E England; Monika Singha; Jennifer T Stocksdale; Marie Heath; Ki-Hong Jang; Sunhee Jung; Karen Ling; Paymann Jafar-Nejad; Jharrayne I McKnight; Leanne N Ho; Osama Al Dalahmah; Richard L M Faull; Joan S Steffan; Jack C Reidling; Cholsoon Jang; Gina Lee; Don W Cleveland; Clotilde Lagier-Tourenne; Robert C Spitale; Leslie M Thompson

doi:10.1038/s41593-024-01850-w

Aberrant splicing in Huntington's disease accompanies disrupted TDP-43 activity and altered m6A RNA modification

Nat Neurosci. 2025 Jan 6. doi: 10.1038/s41593-024-01850-w. Online ahead of print.

Authors

Thai B Nguyen¹, Ricardo Miramontes², Carlos Chillon-Marinas³, Roy Maimon³, Sonia Vazquez-Sanchez³, Alice L Lau⁴, Nicolette R McClure¹, Zhuoxing Wu⁵, Keona Q Wang¹, Whitney E England⁶, Monika Singha⁶, Jennifer T Stocksdale¹, Marie Heath¹, Ki-Hong Jang⁷, Sunhee Jung⁵, Karen Ling⁸, Paymann Jafar-Nejad⁸, Jharrayne I McKnight¹, Leanne N Ho¹, Osama Al Dalahmah⁹, Richard L M Faull^{10

11}, Joan S Steffan⁴, Jack C Reidling², Cholsoon Jang⁵, Gina Lee⁷, Don W Cleveland³, Clotilde Lagier-Tourenne^{12

13}, Robert C Spitale^{14

15}, Leslie M Thompson^{16

17

18

19}

Affiliations

¹ Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA.
² UCI MIND, University of California, Irvine, Irvine, CA, USA.
³ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
⁴ Department of Psychiatry & Human Behavior, University of California, Irvine, Irvine, CA, USA.
⁵ Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, Irvine, CA, USA.
⁶ Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.
⁷ Department of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, Irvine, CA, USA.
⁸ Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA.
⁹ Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
¹⁰ Department of Anatomy and Medical Imaging, Faculty of Medical and Health Science, University of Auckland, Auckland, New Zealand.
¹¹ Centre for Brain Research, Faculty of Medical and Health Science, University of Auckland, Auckland, New Zealand.
¹² Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹³ Broad Institute of Harvard University and MIT, Cambridge, MA, USA.
¹⁴ Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA. rspitale@uci.edu.
¹⁵ Department of Chemistry, University of California, Irvine, Irvine, CA, USA. rspitale@uci.edu.
¹⁶ Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA, USA. lmthomps@hs.uci.edu.
¹⁷ UCI MIND, University of California, Irvine, Irvine, CA, USA. lmthomps@hs.uci.edu.
¹⁸ Department of Psychiatry & Human Behavior, University of California, Irvine, Irvine, CA, USA. lmthomps@hs.uci.edu.
¹⁹ Sue and Bill Gross Stem Cell Center, University of California, Irvine, Irvine, CA, USA. lmthomps@hs.uci.edu.

PMID: 39762660
DOI: 10.1038/s41593-024-01850-w

Abstract

Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene, leading to altered gene expression. However, the mechanisms leading to disrupted RNA processing in HD remain unclear. Here we identify TDP-43 and the N6-methyladenosine (m6A) writer protein METTL3 to be upstream regulators of exon skipping in multiple HD systems. Disrupted nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 occurs in HD mouse and human brains, with TDP-43 also co-localizing with HTT nuclear aggregate-like bodies distinct from mutant HTT inclusions. The binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in the striatum of HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a mechanism underlying alternative splicing in HD.

Abstract

Grants and funding