Author:
Muñoz-Estrada Jesús,Nguyen Abraham V.,Goetz Sarah C.
Abstract
ABSTRACTFrameshift mutations inTau Tubulin Kinase 2(TTBK2) cause spinocerebellar ataxia type 11 (SCA11), which is characterized by the progressive loss of Purkinje cells and cerebellar atrophy. Previous work showed that theseTTBK2variants generate truncated proteins that interfere with primary ciliary trafficking and with Sonic Hedgehog (SHH) signaling in mice. Nevertheless, the molecular mechanisms underlying the dominant interference of mutations remain unknown. Herein, we discover that SCA11-associated variants contain abona fideperoxisomal targeting signal type 1. We find that their expression in RPE1 cells reduces peroxisome numbers within the cell and at the base of the cilia, disrupts peroxisome fission pathways, and impairs trafficking of ciliary SMO upon SHH signaling activation. This work uncovers a neomorphic function of SCA11-causing mutations and identifies requirements for both peroxisomes and cholesterol in trafficking of cilia-localized SHH signaling proteins. In addition, we postulate that molecular mechanisms underlying cellular dysfunction in SCA11 converge on the SHH signaling pathway.SUMMARYMolecular mechanisms underlying spinocerebellar ataxia type 11 are not well understood. In this study, we identified a neomorphic function of the mutated gene (TTBK2) associated with this disease highlighting a functional inter-organelle interaction between peroxisomes and cilia.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
1. The peroxisome: an update on mysteries 3.0;Histochemistry and Cell Biology;2024-01-20