Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia


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.

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Figure 1: Mutations of UBQLN2 in patients with ALS and ALS/dementia.
Figure 2: Ubiquilin-2-immunoreactive inclusions in the spinal cord and hippocampus.
Figure 3: Co-localization of ubiquilin 2 with ALS- and dementia-linked TDP43.
Figure 4: Mutations in ubiquilin 2 lead to ubiquitin-mediated impairment of proteasomal degradation.


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This study was supported by the National Institute of Neurological Disorders and Stroke (NS050641), the Les Turner ALS Foundation, the Vena E. Schaff ALS Research Fund, the Harold Post Research Professorship, the Herbert and Florence C. Wenske Foundation, the David C. Asselin MD Memorial Fund, the Help America Foundation and the Les Turner ALS Foundation/Herbert C. Wenske Foundation Professorship. F.F. has support from NIH (T32 AG20506). K.A. is a postdoctoral fellow of the Blazeman Foundation for ALS. G.H.G. received travel funds from MND Scotland. We thank N. Dantuma for the UPS reporter plasmid (through Addgene) and the staff of the Northwestern University Robert H. Lurie Comprehensive Cancer Center flow cytometry core facility for technical assistance. Imaging work was performed at the Northwestern University Cell Imaging Facility, supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center.

Author information

T.S. conceived and supervised this project. W.C., S.-T.H., Y.Y., H.J., M.H., H.-X.D. and T.S. did the sequencing analysis. S.T.H., E.R., J.L.H., M.P.-V. and T.S. performed linkage analysis. K.M.B., G.H.G., F.F., G.H.J., H.Z., E.H.B., K.A., E.M., H.-X.D. and T.S. performed immunohistochemical, confocal and pathological analysis. F.F., Y.S. and H.-X.D. performed functional analysis. N.S., S.D. and T.S. collected family information and coordinated this study. K.M.B., G.H.J., B.R.B., R.L.S. and T.S. did clinical studies. H.-X.D. and T.S. analysed the data and wrote the paper.

Correspondence to Teepu Siddique.

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Deng, H., Chen, W., Hong, S. et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211–215 (2011) doi:10.1038/nature10353

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