Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation

Abstract

We investigated a family manifesting amyotrophic lateral sclerosis (ALS) with a heterozygous E478G mutation in the optineurin (OPTN) gene. Clinically, slow deterioration of motor function, mood and personality changes, temporal lobe atrophy on neuroimaging, and bizarre finger deformity were noted. Neuropathologically, TAR DNA-binding protein 43 (TDP-43)-positive neuronal intracytoplasmic inclusions were observed in the spinal and medullary motor neurons. In these cells, the immunoreactivity of nuclear TDP-43 was reduced. Consecutive sections revealed that the inclusions were also reactive with anti-ubiquitin and anti-p62 antibodies, but noticeably negative for OPTN. In addition, TDP-43/p62-positive glial cytoplasmic inclusions (GCIs) were scattered throughout the spinal cord and the medullary motor nuclei. Furthermore, Golgi fragmentation was identified in 70% of the anterior horn cells (AHCs). The presence of AHCs with preserved nuclear TDP-43 and a fragmented Golgi apparatus, which are unrecognizable in sporadic ALS, indicates that patients with the E4787G OPTN mutation would manifest Golgi fragmentation before loss of nuclear TDP-43. In the neocortex, GCIs were sparsely scattered among the primary motor and temporal cortices, but no neuronal TDP-43-positive inclusions were detected. In the amygdala and the ambient gyrus, argyrophilic grains and ballooned neurons were seen. The thorough neuropathologic investigations performed in this work demonstrated that OPTN-positive inclusion bodies, if any, were not prominent. We postulate that optineurinopathy is closely linked with TDP-proteinopathy and speculate that this heterozygous E478G mutation would cause ALS by acting through a dominant-negative mechanism.

Mutations in the ubiquitin-binding domain of OPTN/optineurin interfere with autophagy-mediated degradation of misfolded proteins by a dominant-negative mechanism

“…Recently, increased LC3-II content together with defective clearance of IBs has been recognized as an independent measurement of impairment in autophagic flux, and carries similar significance as a defective LC3 turnover. 45 A recent clinical study hypothesizes that the heterozygous E478G mutation likely causes familial ALS through a dominant-negative mechanism; 46 our current study provided experimental evidence to demonstrate that UbBD mutants indeed act as dominativenegative traps, which may have important clinical implications that may guide development for further therapy of diseases mediated by OPTN dysfunction.…”

Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy

“…Thus, the rate at which acutely damaged mitochondria are engulfed by autophagosomes may potently affect cellular homeostasis, with delays leading to toxic cellular insult. Consistent with this possibility, mutations in OPTN cause neurodegeneration, including both ALS and glaucoma, whereas TBK1 mutations also result in ALS and are implicated in frontotemporal dementia (FTD) (17)(18)(19)(20)(21)(22).…”

“…In the past several years, multiple mutations in both OPTN and TBK1 have been identified in patients with ALS and FTD (17)(18)(19)(20)(21)(22). We therefore examined whether these disease-associated mutations interfere with efficient mitophagy.…”

Genetics of Familial Amyotrophic Lateral Sclerosis

“…Conversely, the heterozygous missense substitution is predicted to exert a dominant negative effect. Examination of autopsy derived spinal cord tissue revealed extensive OPTN staining of TDP-43 positive intracytoplasmic hyaline inclusion bodies, although this was not replicated in a subsequent study (Hortobagyi et al 2011;Ito et al 2011b).…”

“…However, the discovery of pathogenic mutations in ALS by linkage analysis is difficult because a relatively low prevalence and rapid disease course make large pedigrees difficult to obtain, therefore novel strategies to identify pathogenic mutations are essential (Hand & Rouleau 2002). With the evolution of next generation sequencing technology, exhaustive sequencing of exonic regions of the genome has been used to identify pathogenic mutations in the VCP gene in ALS, and genetic mutations responsible for other diseases have also been identified from relatively few related or unrelated patients (Bowne et al 2011;Hoischen et al 2010;Johnson et al 2010a;Ng et al 2010;Ng et al 2009;Nikopoulos et al 2010;Simpson et al 2011). Exome sequencing, unlike a linkage analysis and positional cloning approach, is not targeted at a candidate region.…”