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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.

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Acknowledgments

This work was supported in part by grants-in-aid for scientific research from the Japan Society for the Promotion of Science (no. 21500336) and from the Japan Science and Technology Agency (AS2211173G). We thank Professor Yoshifumi Yokota (Department of Biochemistry and Bioinformative Sciences, University of Fukui) for his helpful advice, Drs Makio Takahashi, Kengo Uemura, and Hirofumi Yamashita (Department of Neurology, Kyoto University Graduate School of Medicine) for valuable discussions, Dr Masaya Hashimoto (Takao Hospital) for providing clinical information on Patient III-3, and Miss Hitomi Nakabayashi for her excellent technical assistance.

Conflict of interest

The authors declare they have no conflict of interest.

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Correspondence to Hidefumi Ito.

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Ito, H., Nakamura, M., Komure, O. et al. Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation. Acta Neuropathol 122, 223–229 (2011). https://doi.org/10.1007/s00401-011-0842-y

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Keywords

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