The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP
Anna D. Umano, Kuili Fang, Zhongwei Qu, Jamie B. Scaglione, Selin Altınok, Colton J. Treadway, Elizaveta T. Wick, Ethan Paulаkonis, Chamithi Karunanayake, Samantha Chou, Tanya Bardakjian, Pedro Gonzalez‐Alegre, Richard C. Page, Jonathan C. Schisler, Nicholas G. Brown, Dong Yan, K. Matthew Scaglione
Abstract
point mutant retains E3-ligase activity but has decreased affinity for chaperones. We further show that this mutant decreases cellular fitness in response to certain cellular stressors and induces neurodegeneration in a transgenic Caenorhabditis elegans model of SCA48. Together, our data identify the A52G mutant as a cause of SCA48 and provide molecular insight into how mutations in STUB1 cause SCA48.
Topics & Concepts
Ubiquitin ligaseBiologyTetratricopeptideProteostasisSpinocerebellar ataxiaPoint mutationUbiquitin-Protein LigasesMutantUbiquitinCell biologyDNA ligaseNeurodegenerationProteasomeMutationProtein degradationGeneticsGeneDiseaseMedicinePathologyGenetic Neurodegenerative DiseasesEndoplasmic Reticulum Stress and DiseaseUbiquitin and proteasome pathways