Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia
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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), TAR DNA-binding protein (TARDBP, also known as TDP43) and fused in sarcoma (FUS, also known as translocated in liposarcoma (TLS)) 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 syndromes. 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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UBQLN2 colocalizes with SQSTM1 and ubiquitin in neuronal aggregates characteristic of ALS and ALS-FTD.
“UBQLN2 colocalizes with SQSTM1 and ubiquitin in neuronal aggregates characteristic of both ALS and ALS-FTD [221,224].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [221]
Rare UBQLN2 mutations are associated with familial forms of ALS and ALS-FTD.
“Rare UBQLN2 mutations are associated with familial forms of ALS and ALS-FTD [221–223]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [221]
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- Authors
- Deng, H.-X., Chen, W., Hong, S.-T., Boycott, K. M., Gorrie, G. H., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., Jiang, H., Hirano, M., Rampersaud, E., Jansen, G. H., Donkervoort, S., Bigio, E. H., Brooks, B. R., Ajroud, K., Sufit, R. L., Haines, J. L., Mugnaini, E., Pericak-Vance, M. A., & Siddique, T.
- Affiliations
- Northwestern University (US)
- University of Ottawa (CA)
- University of Miami (US)
- Carolinas Medical Center (US)
- Vanderbilt University (US)
- Corresponding author
- Siddique, Teepu
- ORCID
- Venue
- Nature
- Published
- 2011-08-21
- Volume
- 477
- Issue
- 7363
- Pages
- 211-215
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3169705
- OpenAlex
- W2072981065
- Cited by
- 1,174
- References
- 36
- Citations by year
- 2026: 30 · 2025: 45 · 2024: 56 · 2023: 56 · 2022: 68 · 2021: 76 · 2020: 90 · 2019: 71 · 2018: 83 · 2017: 86 · 2016: 89 · 2015: 88 · 2014: 97 · 2013: 98 · 2012: 103
- FWCI
- 67.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Northwestern University
- Blazeman Foundation for ALS
- MND Scotland
- National Institutes of Health
- Robert H. Lurie Comprehensive Cancer Center
- Japan Society for the Promotion of Science (21591097)
- National Institute on Aging (T32 AG-20506, T32AG020506)
- National Cancer Institute (P30CA060553)
- National Institute of Neurological Disorders and Stroke (R01NS037912, NS050641, R01NS050641)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- amyotrophic lateral sclerosis, UBQLN2, X-linked inheritance, frontotemporal dementia, ubiquitin-like proteins, protein degradation, ubiquitin-proteasome system, protein aggregation, neurodegeneration, familial ALS, sporadic ALS, motor neuron degeneration
- MeSH terms
- Autophagy-Related Proteins, Adult, Aging, Amino Acid Sequence, Amyotrophic Lateral Sclerosis, Base Sequence, Cell Line, Child, Dementia, DNA-Binding Proteins, Female, Genes, Dominant, Hippocampus, Humans, Male, Molecular Sequence Data, Mutation, Pedigree, Spinal Cord, Ubiquitins, Age of Onset, Cell Cycle Proteins, Ubiquitin, Proteasome Endopeptidase Complex, Adaptor Proteins, Signal Transducing, Genes, X-Linked
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