title: TDP-43 is consistently co-localized with ubiquitinated inclusions in sporadic and Guam amyotrophic lateral sclerosis but not in familial amyotrophic lateral sclerosis with and without SOD1 mutations.
abstract: The transactive response (TAR) DNA binding protein 43 (TDP-43) has been recently implicated as a major component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS, motor neuron disease: MND) and ALS-related disorders. In this study, we examined abnormal TDP-43 pathology in 13 sporadic ALS (SALS), six familial ALS (FALS) with and without Cu/Zn superoxide dismutase (SOD1) mutations (SOD1-FALS and non-SOD1-FALS), Guam ALS, two frontotemporal lobar degeneration with MND/ALS (FTLD-MND/ALS), one FTLD with ubiquitin-only-immunoreactive inclusions (FTLD-U) and two progressive supranuclear palsy (PSP). Sections from the spinal cord were processed for immunohistochemistry using antibodies against TDP-43, ubiquitin, p62, cystatin C, phosphorylated tau protein (P-tau; AT8), alpha-synuclein and phosphorylated neurofilament protein (P-NF). In 12 out of 13 SALS and both Guam ALS cases ubiquitin and p62-immunoreactive (IR) neuronal inclusions co-localized with TDP-43. In three out of four SOD1-FALS and one of two non-SOD1-FALS cases, TDP-43-IR inclusions were absent despite the presence of p62 and/or ubiquitin-IR inclusions. However, a single TDP-43-IR neuronal inclusion co-localized with p62 and ubiquitin in one SOD1-FALS (His48Gln) case. Except for one neuron in a Guam case, all TDP-43-IR neuronal inclusions were negative for P-tau (AT8). TDP-43-IR glial inclusions and neurites were also demonstrated. The TDP-43 is a consistent component of the ubiquitinated inclusions in SALS and Guam ALS, but TDP-43-IR inclusions are absent or scarce in SOD1-FALS.
authors.affiliation: Department of Clinical Neuroscience, Medical Research Council Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 9RS, UK.
authors.forename: Satomi
authors.initials: S
authors.lastname: Maekawa
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.forename: Andrew
authors.initials: A
authors.lastname: King
authors.forename: Edith
authors.initials: E
authors.lastname: Jones
authors.forename: John C
authors.initials: JC
authors.lastname: Steele
authors.forename: Istvan
authors.initials: I
authors.lastname: Bodi
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobagyi
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D013482:Superoxide Dismutase