T Onozato1,2, A Nakahara1, E Suzuki-Kouyama1, A Hineno3, T Yasude3, T Nakamura4, H Yahikozawa5, M Watanabe6, K Kayanuma7, H Makishita8, S Ohara9, T Hashimoto1,14, K Higuchi11, T Sakai12, K Asano13, T Hashimoto1,14, H Kanno15, J Nakayama16, K Oyanagi17. 1. Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan. 2. Safety Research Laboratory of Research and Development, Kissei Pharmaceutical Co., Ltd., Nagano, Japan. 3. Department of Neurology, Suwa Red Cross Hospital, Nagano, Japan. 4. Department of Pathology, Suwa Red Cross Hospital, Nagano, Japan. 5. Department of Neurology, Nagano Red Cross Hospital, Nagano, Japan. 6. Department of Pathology, Nagano Red Cross Hospital, Nagano, Japan. 7. Department of Neurology, Ina Central Hospital, Nagano, Japan. 8. Department of Neurology, Hokushin General Hospital, Nagano, Japan. 9. Department of Neurology, Matsumoto Medical Center, Nagano, Japan. 10. Department of Neurology, Aizawa Hospital, Nagano, Japan. 11. Section of Anatomic Pathology, Aizawa Hospital, Nagano, Japan. 12. Department of Neurology, Nagano Matsushiro General Hospital, Nagano, Japan. 13. Department of Pathology, Suwa Chuo Hospital, Nagano, Japan. 14. Department of Neurology, University of Occupational and Environmental Health, Fukuoka, Japan. 15. Department of Pathology, Shinshu University School of Medicine, Nagano, Japan. 16. Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Nagano, Japan. 17. Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan. k123ysm@shinshu-u.ac.jp.
Abstract
AIMS: 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. METHODS: 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. RESULTS: (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. CONCLUSIONS: 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.
AIMS: 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. METHODS: 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. RESULTS: (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. CONCLUSIONS: 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: Adam J Svahn; Emily K Don; Andrew P Badrock; Nicholas J Cole; Manuel B Graeber; Justin J Yerbury; Roger Chung; Marco Morsch Journal: Acta Neuropathol Date: 2018-06-25 Impact factor: 17.088
Authors: Sahara J Cathcart; Stanley H Appel; Leif E Peterson; Ericka P Greene; Suzanne Z Powell; Anithachristy S Arumanayagam; Andreana L Rivera; Matthew D Cykowski Journal: J Neuropathol Exp Neurol Date: 2021-09-10 Impact factor: 3.685