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.
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