Optineurin (OPTN) is a multifunctional protein and its mutations are associated with neurodegenerative diseases such as POAG and amyotrophic lateral sclerosis (ALS).
Optineurin, a cytosolic protein associated with the actin cytoskeleton, microtubules, and the Golgi complex, appears to have an important function in neurons, as mutations in its gene are causative for neurodegenerative diseases such as primary open-angle glaucoma and amyotrophic lateral sclerosis.
OPTN (optineurin) is an autophagy receptor and mutations in the OPTN gene result in familial glaucoma (E50K) and amyotrophic lateral sclerosis (ALS) (E478G).
Optineurin (OPTN) was initially identified as a regulator of NF-κB and interferon signaling, but attracted most attention because of its association with various human disorders such as glaucoma, Paget disease of bone, and amyotrophic lateral sclerosis.
OPTN mutations contribute to ALS in Chinese population and account for 0.8% of sporadic ALS patients and 1.5% of familial ALS in the pooled Chinese ALS cohorts.
Cases C-E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain.
Certain mutations in OPTN (gene <i>OPTN</i>) are associated with primary open angle glaucoma, a leading cause of irreversible blindness, and amyotrophic lateral sclerosis, a fatal motor neuron disease.
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.
In 2010, autosomal recessively inherited mutations in the optineurin (OPTN) gene were found in 1% of Japanese patients with sporadic amyotrophic lateral sclerosis (ALS).
In addition to the C9orf72 expansion, we observed an ATXN2 polyQ intermediate length expansion, and OPTNp.Met468Arg in patients who exhibited ALS and FTD or bvFTD.
In addition, those pathological neurofilament accumulations are known in α-synuclein in Parkinson's disease (PD), Aβ and tau in Alzheimer's disease (AD), polyglutamine in CAG trinucleotide repeat disorders, superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP43), neuronal FUS proteins, optineurin (OPTN), ubiquilin 2 (UBQLN2), and dipeptide repeat protein (DRP) in amyotrophic lateral sclerosis (ALS).
In addition, we also identified 7 potentially pathogenic missense variants that have not been previously reported in ALS patients; this includes 3 novel variants (OPTN: K489E, DAO: E121K, and SETX: L2163V) that are not reported in large population databases and 4 rare variants (CHMP2B: E45K, SQSTM1: G262R and P438L, ERBB4: R103H) with a minor allele frequency of <0.01 in large population databases.
In this work, we report that NF-κB activity was increased in <i>Optn</i> knockout (<i>Optn</i><sup>-/-</sup>) MEF (mouse embryonic fibroblast) cells expressing OPTN of different ALS-associated mutants especially E478G.
In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis.
Inhibition or depletion of TBK1, or expression of amyotrophic lateral sclerosis (ALS)-associated OPTN or TBK1 mutant blocks efficient autophagosome formation.