HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Evidence of a link between ubiquilin 2 and optineurin in amyotrophic lateral sclerosis.

Abstract
A mutation in the ubiquilin 2 gene (UBQLN2) was recently identified as a cause of X-linked amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and a major component of the inclusion bodies commonly found with a wide variety of ALS. ALS-linked mutations in UBQLN2 are clustered in a unique proline-X-X repeat region, reportedly leading to impairment of the ubiquitin proteasome system. However, the molecular properties of mutant UBQLN2 remain unclear. To gain insight into the pathogenesis of UBQLN2-linked ALS/FTD, we examined the biochemical and cellular characteristics of mutant UBQLN2 in vitro. UBQLN2 localized in Rab11-positive endosomal vesicles formed by the ALS-linked molecule optineurin (OPTN). These vesicles were ubiquitin- and p62-immunopositive and also co-localized with an initiator of the autophagic process, ULK1, after amino acid starvation. An ALS-linked mutation (E478G) in OPTN abolished vesicle formation. ALS-linked mutations in UBQLN2 additively enhanced UBQLN2 aggregation and formation of inclusion bodies, resulting in mislocation from OPTN vesicles. UBQLN2 was found to be a potent regulator of the levels of the FTD-linked secretory factor progranulin, possibly via the endosomal system, and ALS-linked mutations disturbed these functional consequences. This study demonstrates that ALS-linked mutations in both OPTN and UBQLN2 interfere with the constitution of specific endosomal vesicles, suggesting that the vesicles are involved in protein homeostasis and that these proteins function in common pathological processes. These data suggest a novel disease spectrum and provide new pathological insights into OPTN and UBQLN2, enhancing our understanding of the molecular basis of ALS/FTD.
AuthorsMayuko Osaka, Daisuke Ito, Takuya Yagi, Yoshihiro Nihei, Norihiro Suzuki
JournalHuman molecular genetics (Hum Mol Genet) Vol. 24 Issue 6 Pg. 1617-29 (Mar 15 2015) ISSN: 1460-2083 [Electronic] England
PMID25398946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • Cell Cycle Proteins
  • Membrane Transport Proteins
  • OPTN protein, human
  • Transcription Factor TFIIIA
  • UBQLN2 protein, human
  • Ubiquitins
Topics
  • Adaptor Proteins, Signal Transducing
  • Amyotrophic Lateral Sclerosis (etiology, genetics)
  • Animals
  • Autophagy-Related Proteins
  • Cell Cycle Proteins (genetics)
  • Chlorocebus aethiops
  • Endosomes (metabolism)
  • Frontotemporal Dementia (etiology, genetics)
  • Humans
  • Inclusion Bodies (metabolism)
  • Membrane Transport Proteins
  • Mice
  • Mutation
  • Transcription Factor TFIIIA (genetics)
  • Ubiquitins (genetics)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: