Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia
Top Cited Papers
Open Access
- 21 August 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 477 (7363), 211-215
- https://doi.org/10.1038/nature10353
Abstract
A study of a five-generation family with the usually fatal disorder amyotrophic lateral sclerosis (ALS) has identified mutations in the UBQLN2 gene, which encodes the ubiquitin-like protein ubiquilin 2, as a cause of ALS and ALS/dementia. This finding is of particular interest as it links familial and sporadic forms of the disease through a ubiquilin 2 pathology observed in the spinal cords of ALS cases and in the brains of ALS/dementia cases with or without UBQLN2 mutations. This novel pathology shows that abnormalities in ubiquilin 2 are associated with defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that might be a target for therapeutic intervention. Amyotrophic lateral sclerosis (ALS) is a paralytic and usually fatal disorder caused by motor-neuron degeneration in the brain and spinal cord. Most cases of ALS are sporadic but about 5–10% are familial. Mutations in superoxide dismutase 1 (SOD1)1,2, TAR DNA-binding protein (TARDBP, also known as TDP43)3,4 and fused in sarcoma (FUS, also known as translocated in liposarcoma (TLS))5,6 account for approximately 30% of classic familial ALS. Mutations in several other genes have also been reported as rare causes of ALS or ALS-like syndromes7,8,9,10,11,12,13,14,15. The causes of the remaining cases of familial ALS and of the vast majority of sporadic ALS are unknown. Despite extensive studies of previously identified ALS-causing genes, the pathogenic mechanism underlying motor-neuron degeneration in ALS remains largely obscure. Dementia, usually of the frontotemporal lobar type, may occur in some ALS cases. It is unclear whether ALS and dementia share common aetiology and pathogenesis in ALS/dementia. Here we show that mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin 2, cause dominantly inherited, chromosome-X-linked ALS and ALS/dementia. We describe novel ubiquilin 2 pathology in the spinal cords of ALS cases and in the brains of ALS/dementia cases with or without UBQLN2 mutations. Ubiquilin 2 is a member of the ubiquilin family, which regulates the degradation of ubiquitinated proteins. Functional analysis showed that mutations in UBQLN2 lead to an impairment of protein degradation. Therefore, our findings link abnormalities in ubiquilin 2 to defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention.This publication has 37 references indexed in Scilit:
- Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALSNeuron, 2010
- Recognition of tandem PxxP motifs as a unique Src homology 3-binding mode triggers pathogen-driven actin assemblyProceedings of the National Academy of Sciences of the United States of America, 2010
- FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degenerationActa Neuropathologica, 2010
- Paraoxonase gene mutations in amyotrophic lateral sclerosisAnnals of Neurology, 2010
- Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidaseProceedings of the National Academy of Sciences of the United States of America, 2010
- Deleterious Variants of FIG4, a Phosphoinositide Phosphatase, in Patients with ALSAmerican Journal of Human Genetics, 2009
- Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar DegenerationActa Neuropathologica, 2007
- Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotypeActa Neuropathologica, 2006
- Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondriaProceedings of the National Academy of Sciences of the United States of America, 2006
- Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosisNature, 1993