Publication Date:
2011-08-23
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169705/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169705/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deng, Han-Xiang -- Chen, Wenjie -- Hong, Seong-Tshool -- Boycott, Kym M -- Gorrie, George H -- Siddique, Nailah -- Yang, Yi -- Fecto, Faisal -- Shi, Yong -- Zhai, Hong -- Jiang, Hujun -- Hirano, Makito -- Rampersaud, Evadnie -- Jansen, Gerard H -- Donkervoort, Sandra -- Bigio, Eileen H -- Brooks, Benjamin R -- Ajroud, Kaouther -- Sufit, Robert L -- Haines, Jonathan L -- Mugnaini, Enrico -- Pericak-Vance, Margaret A -- Siddique, Teepu -- NS050641/NS/NINDS NIH HHS/ -- P30 CA060553/CA/NCI NIH HHS/ -- R01 NS037912/NS/NINDS NIH HHS/ -- R01 NS037912-01/NS/NINDS NIH HHS/ -- R01 NS050641/NS/NINDS NIH HHS/ -- R01 NS050641-01/NS/NINDS NIH HHS/ -- T32AG20506/AG/NIA NIH HHS/ -- England -- Nature. 2011 Aug 21;477(7363):211-5. doi: 10.1038/nature10353.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21857683" target="_blank"〉PubMed〈/a〉
Keywords:
Adult
;
Age of Onset
;
Aging
;
Amino Acid Sequence
;
Amyotrophic Lateral Sclerosis/complications/*genetics/pathology
;
Base Sequence
;
Cell Cycle Proteins/analysis/*genetics
;
Cell Line
;
Child
;
DNA-Binding Proteins/metabolism
;
Dementia/*complications/*genetics/pathology
;
Female
;
Genes, Dominant/*genetics
;
Genes, X-Linked/*genetics
;
Hippocampus/metabolism
;
Humans
;
Male
;
Molecular Sequence Data
;
Mutation/*genetics
;
Pedigree
;
Proteasome Endopeptidase Complex/metabolism
;
Spinal Cord/metabolism
;
Ubiquitin/metabolism
;
Ubiquitins/analysis/*genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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