Isoform-specific reduction of the basic Helix-Loop-Helix transcription factor TCF4 levels in Huntington's disease

Nurm, Kaja, Sepp, Mari, Castany-Pladevall, Carla, Creus-Muncunill, Jordi, Tuvikene, Jürgen, Sirp, Alex, Vihma, Hanna, Blake, Derek J. ORCID: https://orcid.org/0000-0002-5005-4731, Perez-Navarro, Esther and Timmusk, Tõnis 2021. Isoform-specific reduction of the basic Helix-Loop-Helix transcription factor TCF4 levels in Huntington's disease. eNeuro 8 (5) , 0197-21.2021. 10.1523/ENEURO.0197-21.2021

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Abstract

Huntington’s disease (HD) is an inherited neurodegenerative disorder with onset of characteristic motor symptoms at midlife, preceded by subtle cognitive and behavioral disturbances. Transcriptional dysregulation emerges early in the disease course and is considered central to HD pathogenesis. Using wild-type (wt) and HD knock-in mouse striatal cell lines we observed a HD genotype-dependent reduction in the protein levels of transcription factor 4 (TCF4), a member of the basic helix-loop-helix (bHLH) family with critical roles in brain development and function. We characterized mouse Tcf4 gene structure and expression of alternative mRNAs and protein isoforms in cell-based models of HD, and in four different brain regions of male transgenic HD mice (R6/1) from young to mature adulthood. The largest decrease in the levels of TCF4 at mRNA and specific protein isoforms were detected in the R6/1 mouse hippocampus. Translating this finding to human disease, we found reduced expression of long TCF4 isoforms in the postmortem hippocampal CA1 area and in the cerebral cortex of HD patients. Additionally, TCF4 protein isoforms showed differential synergism with the proneural transcription factor ASCL1 in activating reporter gene transcription in hippocampal and cortical cultured neurons. Induction of neuronal activity increased these synergistic effects in hippocampal but not in cortical neurons, suggesting brain region-dependent differences in TCF4 functions. Collectively, this study demonstrates isoform-specific changes in TCF4 expression in HD that could contribute to the progressive impairment of transcriptional regulation and neuronal function in this disease.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license
Publisher:	Society for Neuroscience
ISSN:	2373-2822
Date of First Compliant Deposit:	19 October 2021
Date of Acceptance:	22 August 2021
Last Modified:	16 May 2023 22:45
URI:	https://orca.cardiff.ac.uk/id/eprint/144938

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