2. Academic Validation
  3. Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes

Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes

  • Acta Neuropathol. 2024 May 15;147(1):84. doi: 10.1007/s00401-024-02734-w.
Nicolas Leventoux # 1,  Satoru Morimoto # 1 2 3 4,  Mitsuru Ishikawa 1,  Shiho Nakamura 1 2 3,  Fumiko Ozawa 1 2 3,  Reona Kobayashi 1,  Hirotaka Watanabe 1 2,  Sopak Supakul 1,  Satoshi Okamoto 1,  Zhi Zhou 1,  Hiroya Kobayashi 1 2 3,  Chris Kato 1 2 3,  Yoshifumi Hirokawa 4,  Ikuko Aiba 5,  Shinichi Takahashi 1 2 6,  Shinsuke Shibata 1 7,  Masaki Takao 8,  Mari Yoshida 9,  Fumito Endo 10,  Koji Yamanaka 10,  Yasumasa Kokubo 11,  Hideyuki Okano 12 13 14
Affiliations

Affiliations

  • 1 Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
  • 2 Keio Regenerative Medicine Research Centre, Keio University, Kanagawa, Japan.
  • 3 Division of Neurodegenerative Disease Research, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan.
  • 4 Department of Oncologic Pathology, Mie University Graduate School of Medicine, Mie, Japan.
  • 5 Department of Neurology, NHO, Higashinagoya National Hospital, Aichi, Japan.
  • 6 Department of Neurology and Stroke, International Medical Centre, Saitama Medical University, Saitama, Japan.
  • 7 Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
  • 8 Department of Clinical Laboratory, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan.
  • 9 Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan.
  • 10 Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Aichi, Japan.
  • 11 Kii ALS/PDC Research Centre, Mie University Graduate School of Regional Innovation Studies, Mie, Japan. kokubo7011@gmail.com.
  • 12 Department of Physiology, Keio University School of Medicine, Tokyo, Japan. hidokano@keio.jp.
  • 13 Keio Regenerative Medicine Research Centre, Keio University, Kanagawa, Japan. hidokano@keio.jp.
  • 14 Division of Neurodegenerative Disease Research, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan. hidokano@keio.jp.
  • # Contributed equally.
PMID: 38750212 DOI: 10.1007/s00401-024-02734-w
Abstract

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.

Keywords

Amyotrophic lateral sclerosis (ALS); Astrocyte; CHCHD2; Kii ALS/PDC; Mitochondria; Parkinsonism-dementia complex (PDC).

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