title: Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia.
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), 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.
authors.affiliation: Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: Deng
authors.forename: Wenjie
authors.initials: W
authors.lastname: Chen
authors.forename: Seong-Tshool
authors.initials: ST
authors.lastname: Hong
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: George H
authors.initials: GH
authors.lastname: Gorrie
authors.forename: Nailah
authors.initials: N
authors.lastname: Siddique
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Faisal
authors.initials: F
authors.lastname: Fecto
authors.forename: Yong
authors.initials: Y
authors.lastname: Shi
authors.forename: Hong
authors.initials: H
authors.lastname: Zhai
authors.forename: Hujun
authors.initials: H
authors.lastname: Jiang
authors.forename: Makito
authors.initials: M
authors.lastname: Hirano
authors.forename: Evadnie
authors.initials: E
authors.lastname: Rampersaud
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Jansen
authors.forename: Sandra
authors.initials: S
authors.lastname: Donkervoort
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Brooks
authors.forename: Kaouther
authors.initials: K
authors.lastname: Ajroud
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sufit
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Enrico
authors.initials: E
authors.lastname: Mugnaini
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D017668:Age of Onset; D000375:Aging; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D000071183:Autophagy-Related Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000032:analysis / Q000235:genetics*; D002460:Cell Line; D002648:Child; D004268:DNA-Binding Proteins / Q000378:metabolism; D003704:Dementia / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D050172:Genes, X-Linked / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014452:Ubiquitins / Q000032:analysis / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C405662:UBQLN2 protein, human; D025801:Ubiquitin; D014452:Ubiquitins; D046988:Proteasome Endopeptidase Complex