Mutations of optineurin in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) has its onset in middle age and is a progressive disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord. Most cases of ALS are sporadic, but about 10% are familial. Genes known to cause classic familial ALS (FALS) are superoxide dismutase 1 (SOD1), ANG encoding angiogenin, TARDP encoding transactive response (TAR) DNA-binding protein TDP-43 (ref. 4) and fused in sarcoma/translated in liposarcoma (FUS, also known as TLS). However, these genetic defects occur in only about 20-30% of cases of FALS, and most genes causing FALS are unknown. Here we show that there are mutations in the gene encoding optineurin (OPTN), earlier reported to be a causative gene of primary open-angle glaucoma (POAG), in patients with ALS. We found three types of mutation of OPTN: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Analysis of cell transfection showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B (NF-kappaB), and the E478G mutation revealed a cytoplasmic distribution different from that of the wild type or a POAG mutation. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also noticeably immunolabelled by anti-OPTN antibodies. Our findings strongly suggest that OPTN is involved in the pathogenesis of ALS. They also indicate that NF-kappaB inhibitors could be used to treat ALS and that transgenic mice bearing various mutations of OPTN will be relevant in developing new drugs for this disorder.

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

“…In addition to this, heterozygous and homozygous OPTN mutations have been identified in patients affected with familial, middle‐age‐onset, Amyotrophic Lateral Sclerosis (ALS), a progressive disorder characterized by degeneration of motor neurons of the primary motor cortex (Maruyama et al. 2010; Maruyama and Kawakami 2013), including one study which identified a risk allele for OPTN ‐associated glaucoma in combination with a missense change in another ALS‐associated gene, raising the possibility of digenic inheritance (Weishaupt et al. 2013).…”

EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms

“…In subjects with a deletion (U31, U107, U187 and U198), the deletion points demonstrated the joining of the 5 0 part and 3 0 part with 1-to 8-base-pair microhomology (Figure 1a), which suggests the possibility that these deletions resulted from recombination with unequal crossover. 12 We first evaluated the cellular expression levels of the mutant proteins following forced expression in 293T cells. The result showed that exon deletions (DC185, D143-184, L240Q and DC376-441) and L240Q mutant expressed significantly less protein than did either the wild-type or I363M (Figure 1b, top, indicated by arrowheads), despite a similar level of expression of the corresponding mRNAs (Figure 1b, bottom).…”

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

“…Optineurin (OPTN1) is an autophagy adaptor, whose mutations are linked to ALS (Maruyama et al, 2010;Del Bo et al, 2011). In addition to its roles of degradating foreign pathogens (xenophagy) (Wild et al, 2011) and binding to protein aggregates (Korac et al, 2013), OPTN1 is found in neuronal inclusions of patients affected by ALS and other neurodegenerative diseases (Schwab et al, 2012;Mori et al, 2012).…”

“…The role of OPTN1 in ALS has been further elucidated by the recent discovery of loss of function mutations in TBK1 gene in familial ALS cases (Cirulli et al, 2015). The interaction between TBK1 and OPTN1 is a key factor in autophagy and inflammation (Maruyama et al, 2010;Maruyama and Kawakami, 2013;Thomas et al, 2013;Kachaner et al, 2012). TBK1 enhances the autophagic turnover of bacteria-bound ubiquitylated proteins (Wild et al, 2011;Gleason et al, 2011), through the phosphorylation of OPTN and SQSTM1 (Morton et al, 2008;Pilli et al, 2012) and promoting the interaction of OPTN with LC3.…”