Abstract
Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. For many affected patients, the genetic cause remains undetermined. Through whole-exome sequencing, we identified compound heterozygous mutations in ubiquitin-like modifier activating enzyme 5 gene (UBA5) in two Chinese siblings presenting with ARCA. Moreover, copy number variations in UBA5 or ubiquitin-fold modifier 1 gene (UFM1) were documented with the phenotypes of global developmental delays and gait disturbances in the ClinVar database. UBA5 encodes UBA5, the ubiquitin-activating enzyme of UFM1. However, a crucial role for UBA5 in human neurological disease remains to be reported. Our molecular study of UBA5-R246X revealed a dramatically decreased half-life and loss of UFM1 activation due to the absence of the catalytic cysteine Cys250. UBA5-K310E maintained its interaction with UFM1, although with less stability, which may affect the ability of this UBA5 mutant to activate UFM1. Drosophila modeling revealed that UBA5 knockdown induced locomotive defects and a shortened lifespan accompanied by aberrant neuromuscular junctions (NMJs). Strikingly, we found that UFM1 and E2 cofactor knockdown induced markedly similar phenotypes. Wild-type UBA5, but not mutant UBA5, significantly restored neural lesions caused by the absence of UBA5. The finding of a UBA5 mutation in cerebellar ataxia suggests that impairment of the UFM1 pathway may contribute to the neurological phenotypes of ARCA.
Highlights
Autosomal recessive cerebellar ataxias (ARCAs) are a large group of neurodegenerative disorders that manifest mainly in children and young adults
The disease progressed insidiously in the proband (II:2), who presented with marked cerebellar atrophy as determined by brain magnetic resonance imaging (MRI; Fig 1B), leading to a loss of the ability to walk and caregiver dependency at 39 years of age
The disease course was apparently stable in the younger brother (II:3), who was 36 years old, worked fulltime, and displayed a mildly spastic gait that did not interfere with his daily activities, and exhibited mild cerebellar atrophy on MRI
Summary
Autosomal recessive cerebellar ataxias (ARCAs) are a large group of neurodegenerative disorders that manifest mainly in children and young adults. UFM1 is an ubiquitin-like protein (UBL) that, upon activation by a dedicated E1 (UBA5), forms a thioester bond with an E2 cofactor (UFC1), resulting in the tagging of reactive ubiquityl units to substrates by an E3 ligase (UFL1).[7,8,9,10,11] In ischemic myocardial cells and pancreatic islet beta cells, endoplasmic reticulum (ER) stress can induce the expression of UFM1 cascade members, suggesting the protection of the UFM1 cascade during cellular homeostasis.[12,13] In UBA5, the catalytic cysteine (Cys250) is part of the adenylation domain within the helical motif through which the ubiquityl-enzyme thioester is formed.[14] Our cellular studies revealed that both of the two mutants (p.R246X and p.K310E) became less stable which caused reduced enzymatic activity of UBA5. We studied a cohort of patients with ARCA and identified UBA5 mutations in these patients
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
