title: Optineurin inclusions occur in a minority of TDP-43 positive ALS and FTLD-TDP cases and are rarely observed in other neurodegenerative disorders.
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.
authors.affiliation: Department of Clinical Neuroscience, King's College London, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, De Crespigny Park, London SE58AF, UK. tibor.hortobagyi@kcl.ac.uk
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobágyi
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.forename: Agnes L
authors.initials: AL
authors.lastname: Nishimura
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.forename: John C
authors.initials: JC
authors.lastname: van Swieten
authors.forename: Harro
authors.initials: H
authors.lastname: Seelaar
authors.forename: Andrew
authors.initials: A
authors.lastname: King
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.forename: Boris
authors.initials: B
authors.lastname: Rogelj
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000473:pathology*; D017442:Histamine Agonists / Q000378:metabolism; D006801:Humans; D007211:Indoles; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D035582:Transcription Factor TFIIIA / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017442:Histamine Agonists; D007211:Indoles; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C409460:OPTN protein, human; C000606290:SOD1 protein, human; C498585:TUBB3 protein, human; D035582:Transcription Factor TFIIIA; D014404:Tubulin; C007293:DAPI; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1