Abstract
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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Acknowledgements
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
Author notes
- Seong-Tshool Hong
- , George H. Gorrie
- , Hujun Jiang
- & Makito Hirano
Present addresses: Laboratory of Genetics and Department of Microbiology, Chonbuk National University Medical School, Chonbuk 561-712, South Korea (S.-T.H.); Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, UK (G.H.G.); Department of Health Sciences, National Natural Science Foundation of China, Beijing 100085, China (H.J.); Department of Neurology, Sakai Hospital Kinki University Faculty of Medicine, Osaka 590-0132, Japan (M.H.).
- Han-Xiang Deng
- & Wenjie Chen
These authors contributed equally to this work.
Affiliations
Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
- Han-Xiang Deng
- , Wenjie Chen
- , Seong-Tshool Hong
- , George H. Gorrie
- , Nailah Siddique
- , Yi Yang
- , Faisal Fecto
- , Yong Shi
- , Hong Zhai
- , Hujun Jiang
- , Makito Hirano
- , Sandra Donkervoort
- , Kaouther Ajroud
- , Robert L. Sufit
- & Teepu Siddique
Department of Pediatrics, University of Ottawa and Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario K1H 8L1, Canada
- Kym M. Boycott
Interdepartmental Neuroscience Program, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
- Faisal Fecto
- , Enrico Mugnaini
- & Teepu Siddique
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida 33136, USA
- Evadnie Rampersaud
- & Margaret A. Pericak-Vance
Division of Anatomic Pathology, The Ottawa Hospital, Ottawa, Ontario K1Y 4E9, Canada
- Gerard H. Jansen
Division of Neuropathology, Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
- Eileen H. Bigio
Department of Neurology, Neuroscience and Spine Institute, Carolinas Medical Center, Charlotte, North Carolina 28207, USA
- Benjamin R. Brooks
Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee 37232, USA
- Jonathan L. Haines
Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
- Enrico Mugnaini
- & Teepu Siddique
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Contributions
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.
Competing interests
The authors declare no competing financial interests.
Corresponding author
Correspondence to Teepu Siddique.
Supplementary information
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Supplementary Information
The file contains Supplementary Figures 1-18 with legends, Supplementary Tables 1-2 and Supplementary Case Notes.
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