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

By H. Deng, Wenjie Chen, Seong-Tshool Hong, K. Boycott, G. Gorrie, N. Siddique, Yi Yang, Faisal Fecto, Yong Shi, H. Zhai and 13 more. Nature, 2011

1,191 citations recorded by the source corpus.

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.

View Paper: https://www.semanticscholar.org/paper/be299bedc01c83a97f014b130d8ab66f37ea9c88

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Citations in the corpus

Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis (2013, unknown): “Transport of ubiquinated proteins to proteasome polyubiquitin p62 UBQLN2 misfolded proteins Target specification for autophagy LC3 LC3 LC3 adaptor adaptor phagophore p62 p62 OPTN Sorting endosomal cargo for degradation CHMP2B ESCRT III cell membrane protein ubiquitin to autophagy protein aggregates ”
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis (2019, unknown): “, 2016), UBQLN2 and UBQLN4 (Ubiquilin 2 and Ubiquilin 4) (Deng et al., 2011; Edens et al., 2017), NEK1 (NIMA-like kinase 1) (Brenner et al.”
The Logic of the 26S Proteasome. (2017, unknown): “For example, mutations in UBQLN2 (a Dsk2 homolog) cause amyo- trophic lateral sclerosis (ALS) (Deng et al., 2011), and thus it must serve some distinct role, probably in ubiquitylation and shuttling of client proteins to the 26S (Itakura et al., 2016).”
Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration (2011, background): “One important recent finding that may help to clarify the role of altered ubiquitylation (and consequently, of impaired protein degradation) in FTLD-TDP and ALS is the identification of rare dominant missense mutations within ubiquilin 2 ( UBQLN2 ) that are associated with X-linked AL”