The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP

• DOI: 10.1016/j.jbc.2022.101899
• Publication Date: 2022-04-07T05:56:18Z
• Authors: A. Umano; K. Fang; Z. Qu; J.B. Scaglione; S. Altinok; C.J. Treadway; E.T. Wick; E. Paulakonis; C. Karunanayake; S. Chou; T.M. Bardakjian; P. Gonzalez-Alegre; R.C. Page; J.C. Schisler; N.G. Brown; D. Yan; K.M. Scaglione
• Keywords: Tetratricopeptide; Proteostasis; Ubiquitin-Protein Ligases; Protein Degradation

The spinocerebellar ataxias (SCAs) are a class of incurable diseases characterized by degeneration the cerebellum that results in movement disorder. Recently, new heritable form SCA, ataxia type 48 (SCA48), was attributed to dominant mutations STIP1 homology and U box-containing 1 (STUB1); however, little is known about how these cause SCA48. STUB1 encodes for protein C terminus Hsc70 interacting (CHIP), an E3 ubiquitin ligase. CHIP regulate proteostasis recruiting chaperones via N-terminal tetratricopeptide repeat domain E2 ubiquitin-conjugating enzymes C-terminal U-box domain. These interactions allow mediate ubiquitination chaperone-bound, misfolded proteins promote their degradation proteasome. Here we have identified novel, de novo mutation patient with SCA48 encoding A52G point CHIP. Utilizing array biophysical, biochemical, cellular assays, demonstrate CHIPA52G mutant retains E3-ligase activity but has decreased affinity chaperones. We further show this decreases fitness response certain stressors induces neurodegeneration transgenic Caenorhabditis elegans model Together, our data identify as provide molecular insight into