title: Axonal TDP-43 aggregates in sporadic amyotrophic lateral sclerosis.
abstract: Axonal aggregates of phosphorylated (p-) transactive response DNA-binding protein 43 kDa (TDP-43) in sporadic amyotrophic lateral sclerosis (sALS) were examined in relation to propagation of the protein in the nervous system.
  
  
  
  Brains and spinal cords of Japanese patients with sALS and control subjects were examined immunohistochemically using formalin-fixed paraffin-embedded specimens with special reference to the topographical distribution, microscopic features, presynaptic aggregates, and correlation between the aggregates in axons and the clinical course.
  
  
  
  (i) Aggregates of p-TDP-43 were frequently present in axons of the hypoglossal and facial nerve fibres and the spinal anterior horn cells. (ii) Aggregates of p-TDP-43 in the axons showed two characteristic microscopic features - dash-like granuloreticular aggregates (GRAs) and massive aggregates (MAs). (iii) MAs were surrounded by p-neurofilaments, but p-neurofilament immunnoreactivity decreased at the inside of axons with GRAs. (iv) Patients showing MAs and GRAs had a relatively shorter clinical course than patients without the aggregates. (v) Some neurones in the red nucleus in patients were surrounded by synapses containing p- and p-independent (i)-TDP-43, and almost all neurones had lost their nuclear TDP-43 immunoreactivity; 17% of those neurones in the red nucleus also had TDP-43-immunopositive neuronal cytoplasmic inclusions, but no postsynaptic p-TDP-43 deposition was evident.
  
  
  
  There are two types of axonal p-TDP-43 aggregates, MAs and GRAs, located predominantly in the facial and hypoglossal nuclei and anterior horn cells. These aggregates may influence the function of neurones, and presynaptic aggregates of the protein induce loss of p-i-TDP-43 in the nuclei of postsynaptic neurones.
authors.affiliation: Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan.|Safety Research Laboratory of Research and Development, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Onozato
authors.affiliation: Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nakahara
authors.affiliation: Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Suzuki-Kouyama
authors.affiliation: Department of Neurology, Suwa Red Cross Hospital, Nagano, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Hineno
authors.affiliation: Department of Neurology, Suwa Red Cross Hospital, Nagano, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yasude
authors.affiliation: Department of Pathology, Suwa Red Cross Hospital, Nagano, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Neurology, Nagano Red Cross Hospital, Nagano, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yahikozawa
authors.affiliation: Department of Pathology, Nagano Red Cross Hospital, Nagano, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Neurology, Ina Central Hospital, Nagano, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kayanuma
authors.affiliation: Department of Neurology, Hokushin General Hospital, Nagano, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Makishita
authors.affiliation: Department of Neurology, Matsumoto Medical Center, Nagano, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ohara
authors.affiliation: Department of Neurology, Aizawa Hospital, Nagano, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Section of Anatomic Pathology, Aizawa Hospital, Nagano, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Higuchi
authors.affiliation: Department of Neurology, Nagano Matsushiro General Hospital, Nagano, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Department of Pathology, Suwa Chuo Hospital, Nagano, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Asano
authors.affiliation: Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan.|Department of Neurology, University of Occupational and Environmental Health, Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Department of Pathology, Shinshu University School of Medicine, Nagano, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kanno
authors.affiliation: Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Nagano, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Nakayama
authors.affiliation: Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan. k123ysm@shinshu-u.ac.jp.
authors.forename: K
authors.initials: K
authors.lastname: Oyanagi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D044466:Asian People; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human
keywords: amyotrophic lateral sclerosis; axonal aggregate; synapse; topography; transactive response DNA-binding protein 43 kDa