Intracellular dynamics of Ataxin-2 in the human brains with normal and frontotemporal lobar degeneration with TDP-43 inclusions

Acta Neuropathologica Communications

Takashi Nonaka¹  Masato Hasegawa¹  Haruhiko Akiyama²  Ito Kawakami³  Ryohei Watanabe⁴  Kenichi Oshima⁵  Kazuhiro Niizato⁵  Tetsuaki Arai⁶  Shinji Higashi⁷  Mari Yoshida⁸ 

[1] Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, Japan;Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, Japan;Department of Clinical Research, Yokohama Brain and Spine Center, 1-2-1 Takigashira, Isogo, Yokohama, Kanagawa, Japan;Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, Japan;Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, 2-1-1 Kamikitazawa, Setagaya, Tokyo, Japan;Brain Bank for Aging Research, Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi, Tokyo, Japan;Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, Japan;Department of Psychiatry, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan;Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, 2-1-1 Kamikitazawa, Setagaya, Tokyo, Japan;Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, 2-1-1 Kamikitazawa, Setagaya, Tokyo, Japan;Department of Psychiatry, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan;Department of Psychiatry, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan;Department of Psychiatry, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami, Inashiki, Ibaraki, Japan;Institute for Medical Science of Aging, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, Japan;

关键词: RNA-binding protein;    Ataxin-2;    Localization;    TDP-43;    Proteinopathy;    Neurodegeneration;    Amyotrophic lateral sclerosis;    Frontotemporal lobar degeneration;   

DOI  :  10.1186/s40478-020-01055-9

来源: Springer

【 摘 要 】

TAR DNA-binding protein of 43 kDa (TDP-43) is a major component of intracellular aggregates formed in brains of the patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), which are correctively referred to as TDP-43 proteinopathies. A link between Ataxin-2 (ATXN2) and TDP-43 proteinopathies was established when intermediate CAG repeat expansions of ATXN2 gene were found to be associated with ALS and it was shown that ATXN2 modifies TDP-43 toxicity. Although ATXN2’s contribution to TDP-43 proteinopathies has been mostly studied in ALS, recent studies have shown that intermediate repeat expansions of ATXN2 also influence the phenotype of FTLD by an unknown mechanism. To address this issue, we immunohistochemically and biochemically analyzed the intracellular dynamics of ATXN2 in brains of normal controls and FTLD-TDP cases. The immunohistochemical studies revealed that ATXN2 localized in the neuronal cytoplasm and proximal dendrites, and expressed widely and uniformly in normal human brains. A semi-quantitative immunofluorescent analysis of normal brains revealed that the cytoplasmic ATXN2 strongly associates with ribosomal protein S6 and poly-A binding protein 1 and partially overlaps with the endoplasmic reticulum marker Calnexin, suggesting a major role of ATXN2 in protein synthesis. The results of immunohistochemical and biochemical analyses of brains from FTLD-TDP cases showed the colocalization of ATXN2 and phosphorylated TDP-43 in the dystrophic neurites and the neuronal cytoplasmic inclusions in the hippocampal region, and a significant reduction of ATXN2 protein compared to controls. These results suggest that ATXN2 is involved in the pathological process of FTLD-TDP. It remains to be clarified whether reduced ATXN2 expression induces neurodegeneration by impairing protein synthesis or plays a neuroprotective role by attenuating the toxicity of TDP-43 aggregates in FTLD-TDP and other TDP-43 proteinopathies.

【 授权许可】

CC BY