Optineurin inclusions occur in a minority of TDP-43 positive ALS and FTLD-TDP cases and are rarely observed in other neurodegenerative disorders

Tibor Hortobágyi, Claire Troakes, Agnes L. Nishimura, Caroline Vance, John C. Van Swieten, Harro Seelaar, Andrew King, Safa Al-Sarraj, Boris Rogelj, Christopher E. Shaw

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55 Citations (Scopus)

Abstract

Optineurin (OPTN) is a multifunctional protein involved in vesicular trafficking, signal transduction and gene expression. OPTN mutations were described in eight Japanese patients with familial and sporadic amyotrophic lateral sclerosis (FALS, SALS). OPTN-positive inclusions co-localising with TDP-43 were described in SALS and in FALS with SOD-1 mutations, potentially linking two pathologically distinct pathways of motor neuron degeneration. We have explored the abundance of OPTN inclusions using a range of antibodies in postmortem tissues from 138 cases and controls including sporadic and familial ALS, frontotemporal lobar degeneration (FTLD) and a wide range of neurodegenerative proteinopathies. OPTN-positive inclusions were uncommon and detected in only 11/32 (34%) of TDP-43-positive SALS spinal cord and 5/15 (33%) of FTLD-TDP. Western blot of lysates from FTLD-TDP frontal cortex and TDP-43-positive SALS spinal cord revealed decreased levels of OPTN protein compared to controls (p < 0.05), however, this correlated with decreased neuronal numbers in the brain. Large OPTN inclusions were not detected in FALS with SOD-1 and FUS mutation, respectively, or in FTLD-FUS cases. OPTN-positive inclusions were identified in a few Alzheimer's disease (AD) cases but did not co-localise with tau and TDP-43. Occasional striatal neurons contained granular cytoplasmic OPTN immunopositivity in Huntington's disease (HD) but were absent in spinocerebellar ataxia type 3. No OPTN inclusions were detected in FTLD-tau and α-synucleinopathy. We conclude that OPTN inclusions are relatively rare and largely restricted to a minority of TDP-43 positive ALS and FTLD-TDP cases. Our results do not support the proposition that OPTN inclusions play a central role in the pathogenesis of ALS, FTLD or any other neurodegenerative disorder.

Original languageEnglish
Pages (from-to)519-527
Number of pages9
JournalActa neuropathologica
Volume121
Issue number4
DOIs
Publication statusPublished - Apr 2011

Keywords

  • Amyotrophic lateral sclerosis (ALS)
  • Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP)
  • Immunohistochemistry
  • Motor neurone disease (MND)
  • Optineurin (OPTN)
  • Western blotting

ASJC Scopus subject areas

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

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  • Cite this

    Hortobágyi, T., Troakes, C., Nishimura, A. L., Vance, C., Van Swieten, J. C., Seelaar, H., King, A., Al-Sarraj, S., Rogelj, B., & Shaw, C. E. (2011). Optineurin inclusions occur in a minority of TDP-43 positive ALS and FTLD-TDP cases and are rarely observed in other neurodegenerative disorders. Acta neuropathologica, 121(4), 519-527. https://doi.org/10.1007/s00401-011-0813-3