Abstract
YAP and its neuronal isoform YAPdeltaC are implicated in various cellular functions. We found that expression of YAPdeltaC during development, but not adulthood, rescued neurodegeneration phenotypes of mutant ataxin-1 knock-in (Atxn1-KI) mice. YAP/YAPdeltaC interacted with RORα via the second WW domain and served as co-activators of its transcriptional activity. YAP/YAPdeltaC formed a transcriptional complex with RORα on cis-elements of target genes and regulated their expression. Both normal and mutant Atxn1 interacted with YAP/YAPdeltaC, but only mutant Atxn1 depleted YAP/YAPdeltaC from the RORα complex to suppress transcription on short timescales. Over longer periods, mutant Atxn1 also decreased RORα in vivo. Genetic supplementation of YAPdeltaC restored the RORα and YAP/YAPdeltaC levels, recovered YAP/YAPdeltaC in the RORα complex and normalized target gene transcription in Atxn1-KI mice in vivo. Collectively, our data suggest that functional impairment of YAP/YAPdeltaC by mutant Atxn1 during development determines the adult pathology of SCA1 by suppressing RORα-mediated transcription.
Highlights
YAP and its neuronal isoform YAPdeltaC are implicated in various cellular functions
We previously showed that the transcriptional co-factor YAP is involved in an atypical form of necrosis induced by alpha-amanitin, transcriptional repression-induced atypical cell death (TRIAD) in which C-terminal truncated isoforms of YAP play critical roles[13]
The results revealed that YAPdeltaC-ins[61] had the strongest anti-TRIAD activity
Summary
YAP and its neuronal isoform YAPdeltaC are implicated in various cellular functions. We found that expression of YAPdeltaC during development, but not adulthood, rescued neurodegeneration phenotypes of mutant ataxin-1 knock-in (Atxn1-KI) mice. YAP/YAPdeltaC formed a transcriptional complex with RORα on cis-elements of target genes and regulated their expression. Our data suggest that functional impairment of YAP/YAPdeltaC by mutant Atxn[1] during development determines the adult pathology of SCA1 by suppressing RORα-mediated transcription. Spinocerebellar ataxia type 1 (SCA1) is a neurological disease that mainly affects Purkinje cells in the cerebellum and motoneurons in the spinal cord[1,2,3]. It has been more than 20 years since the discovery of the causative gene, Ataxin-1 (ATXN1)[4]. Biochemical and morphological data support the idea that TRIAD occurs in human Huntington’s disease brains[14], and overexpression of YAPdeltaC prevents TRIAD in Huntington’s disease in vitro models[15]
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