title: FUS/TLS-immunoreactive neuronal and glial cell inclusions increase with disease duration in familial amyotrophic lateral sclerosis with an R521C FUS/TLS mutation.
abstract: Basophilic inclusions (BIs) are pathological features of a subset of frontotemporal lobar degeneration disorders, including sporadic amyotrophic lateral sclerosis (ALS) and familial ALS (FALS). Mutations in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene have recently been identified as a cause of FALS. The FUS/TLS-immunoreactive inclusions are consistently found in cases of frontotemporal lobar degeneration with BIs; however, the association between ALS cases with BIs and FUS/TLS accumulation is not well understood. We used immunohistochemistry to analyze 3 autopsy cases of FALS with the FUS/TLS mutation and with BIs using anti-FUS/TLS antibodies. The disease durations were 1, 3, and 9 years. As the disease duration becomes longer, there were broader distributions of neuronal and glial FUS/TLS-immunoreactive inclusions. As early as 1 year after the onset, BIs, neuronal cytoplasmic inclusions and glial cytoplasmic inclusions were found in the substantia nigra in addition to the anterior horn of the spinal cord. Glial cytoplasmic inclusions are found earlier and in a wider distribution than neuronal cytoplasmic inclusions. The distribution of FUS/TLS-immunoreactive inclusions in FUS/TLS-mutated FALS with BIs was broader than that of BIs alone, suggesting that the pathogenetic mechanism may have originated from the FUS/TLS proteinopathy.
authors.affiliation: Department of Neurology, Tohoku University School of Medicine, Sendai, Japan. naoki@med.tohoku.ac.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Suzuki
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kato
authors.forename: Masako
authors.initials: M
authors.lastname: Kato
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Warita
authors.forename: Hideki
authors.initials: H
authors.lastname: Mizuno
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kato
authors.forename: Naoko
authors.initials: N
authors.lastname: Shimakura
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Zen
authors.initials: Z
authors.lastname: Kobayashi
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Konno
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001120:Arginine / Q000235:genetics; D001921:Brain / Q000473:pathology; D003545:Cysteine / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS; D025801:Ubiquitin; D001120:Arginine; D003545:Cysteine