Mutations in UBQLN2 cause Lou Gehrig's Disease

[EDDIEKIRK]

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 510% 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 syndromes^{7, 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 ubiquilin2, cause dominantly inherited, chromosome-X-linked ALS and ALS/dementia. We describe novel ubiquilin2 pathology in the spinal cords of ALS cases and in the brains of ALS/dementia cases with or without UBQLN2 mutations. Ubiquilin2 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 ubiquilin2 to defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention.

[EDDIEKIRK]

UBQLN2



This gene encodes a ubiquitin-like protein (ubiquilin) that shares high degree of similarity with related products in yeast, rat and frog. Ubiquilins contain a N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. They physically associate with both proteasomes and ubiquitin ligases, and are thus thought to functionally link the ubiquitination machinery to the proteasome to effect in vivo protein degradation. This ubiquilin has also been shown to bind the ATPase domain of the Hsp70-like Stch protein.[2





In a small proportion of familial amyotrophic lateral sclerosis (fALS), the UBQLN2 gene is mutated, causing formation of a non-functional Ubiquilin 2 enzyme. This non-functioning enzyme leads to the accumulation of ubiquinated proteins in the lower motor neurons and upper corticospinal motor neurons, due to the fact that ubiquilin 2 normally degrades these ubiquinated proteins, but cannot if the ALS mutation is present. ^[3] The same accumulations occur in patients without UBQLN2 mutations, but with mutations in other genes, including TDP-43 and C9ORF72.



http://en.wikipedia.org/wiki/UBQLN2





Overview
Increases the half-life of proteins destined to be degraded by the proteasome; may modulate proteasome-mediated protein degradation.

function Protein binding<a>definition</a>[GO:0005515]

<div>According to KEGG, this protein belongs to the following pathway:</div>
Protein processing in endoplasmic reticulumhsa04141+29978