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.
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Acknowledgments
This work was supported in the UK by grants from Motor Neurone Disease Association UK; Medical Research Council UK; Wellcome Trust UK; The Psychiatry Research Trust of the Institute of Psychiatry; National Institute for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, King’s College London. The authors declare that they have no conflict of interest. The postmortem tissues were provided by the MRC London Neurodegenerative Diseases Brain Bank at the Institute of Psychiatry, King’s College London. We are thankful for the patients and their families who contributed to this research by giving consent for tissue donation for diagnosis and research. Technical assistance was provided by Christopher Bell, Vasiliki Spandoni, Olar Adeyi, Rita Monori and Marinela Vavla. We thank Emma Daniel and Hazel Urwin for helpful discussions and advice.
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T. Hortobágyi, C. Troakes and A. L. Nishimura contributed equally to this work.
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Hortobágyi, T., Troakes, C., Nishimura, A.L. et al. Optineurin inclusions occur in a minority of TDP-43 positive ALS and FTLD-TDP cases and are rarely observed in other neurodegenerative disorders. Acta Neuropathol 121, 519–527 (2011). https://doi.org/10.1007/s00401-011-0813-3
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DOI: https://doi.org/10.1007/s00401-011-0813-3