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

Hidefumi Ito, Masataka Nakamura, Osamu Komure, Takashi Ayaki, Reika Wate, Hirofumi Maruyama, Yoshimi Nakamura, Kengo Fujita, Satoshi Kaneko, Yoko Okamoto, Masafumi Ihara, Tetsuro Konishi, Kazumasa Ogasawara, Asao Hirano, Hirofumi Kusaka, Ryuji Kaji, Ryosuke Takahashi, Hideshi Kawakami

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)223-229
Number of pages7
JournalActa neuropathologica
Volume122
Issue number2
DOIs
StatePublished - Aug 1 2011

Keywords

  • Amyotrophic lateral sclerosis
  • Golgi fragmentation
  • Optineurin
  • TDP-43

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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