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).
Notably, mutations in the LIR-motif proteins p62 (SQSTM1) and optineurin (OPTN) contribute to familial forms of frontotemporal dementia and amyotrophic lateral sclerosis.
Several mutations in the gene encoding optineurin (OPTN), the receptor for Parkin-dependent mitochondrial autophagy (mitophagy), are associated with glaucoma and amyotrophic lateral sclerosis (ALS).
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.
Remarkably, despite the large degree of heterogeneity, all cases of ALS have protein aggregates in the brain and spinal cord that are immunopositive for SOD1, TDP-43, OPTN, and/or p62.
Mutations in a ubiquitin (Ub)-binding adaptor protein optineurin have been found in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with a prominent neuroinflammatory component.
Regarding its disease associations, mutations in the optineurin gene are associated with glaucoma and have more recently been found to correlate with Paget's disease of bone and amyotrophic lateral sclerosis (ALS).
This case report illustrates the diverse inheritance patterns and variable clinical presentations associated with OPTN mutations, and underscores the importance of complete OPTN gene screening in patients with ALS and related disorders, especially in the context of clinical genetic testing.
Mutations of <i>Optn</i> are associated with normal tension glaucoma and amyotrophic lateral sclerosis, and its gene has also been linked to the development of Paget's disease of bone and Crohn's disease.
We examined the TDP-43, tau, and α-synuclein pathology of ALS cases with OPTN mutations including 2 previously reported cases (Cases 1 and 2) and 1 newly autopsied case (Case 3) that was clinically diagnosed as ALS and Parkinson disease with a heterozygous E478GOPTN mutation.
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 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.
The findings suggest that changes in their accumulation, determined via quantitative comparison of the OPTN foci and IBs in the cells, are involved in pathological features of ALS.
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.
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.
When yeast genetic interaction partners held in common between human OPTN and ANG were validated in mammalian cells and zebrafish, MAP2K5 kinase emerged as a potential drug target for ALS therapy.
Moreover, functional studies of the ALS-causing optineurin mutations and the recently established optineurin ubiquitin-binding deficient and knockout mouse models helped identify three major mechanisms likely to mediate neuroprotection: regulation of autophagy, mitigation of (chronic) inflammatory signaling, and blockade of necroptosis.
Mutations in optineurin (OPTN) are associated with several human disorders including amyotrophic lateral sclerosis (ALS) and primary open-angle glaucoma (POAG).