Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington's Disease

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 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 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 post-mortem 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. Significance Statement Historically, HD has been considered a neurodegenerative disease. However, research of the last decade has revealed disrupted neurogenesis and cognitive dysfunction preceding pathological neuronal cell death, suggesting that HD is also a neurodevelopmental disease. One of the major molecular mechanisms of HD is dysregulation of transcription. Studying transcription factors with functions in neurogenesis and neural plasticity is of interest for their potential participation in the cognitive impairment in HD etiology. Here we show reduced expression of the transcription factor TCF4, previously linked with neurodevelopmental and neuropsychiatric diseases, in hippocampus and cerebral cortex of R6/1 mouse and HD patients. Our results shed light on the potential neurodevelopmental aspect of HD, and could be applicable for developing alleviating therapies for HD.