期刊
ACTA NEUROPATHOLOGICA
卷 121, 期 4, 页码 519-527出版社
SPRINGER
DOI: 10.1007/s00401-011-0813-3
关键词
Amyotrophic lateral sclerosis (ALS); Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP); Immunohistochemistry; Motor neurone disease (MND); Optineurin (OPTN); Western blotting
资金
- Motor Neurone Disease Association UK
- Medical Research Council UK
- Wellcome Trust UK
- Psychiatry Research Trust of the Institute of Psychiatry
- National Institute for Health Research Biomedical Research Centre for Mental Health at the South London
- Maudsley National Health Service Foundation Trust
- Institute of Psychiatry, King's College London
- Medical Research Council [G0900688, MC_G1000733, G0600676, G0500289B, G0500289] Funding Source: researchfish
- MRC [G0500289, MC_G1000733, G0900688, G0600676] Funding Source: UKRI
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 alpha-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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