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Neurodegeneration-associated mitochondrial proteins, CHCHD2 and CHCHD10-what distinguishes the two?

ABSTRACT: Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and Coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) are mitochondrial proteins that are thought to be genes which duplicated during evolution and are the causative genes for Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal lobe dementia, respectively. CHCHD2 forms a heterodimer with CHCHD10 and a homodimer with itself, both of which work together within the mitochondria. Various pathogenic and disease-risk variants have been identified; however, how these mutations cause neurodegeneration in specific diseases remains a mystery. This review focuses on important new findings published since 2019 and discusses avenues to solve this mystery.

SUBMITTER: Ikeda A

PROVIDER: S-EPMC9500460 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Neurodegeneration-associated mitochondrial proteins, CHCHD2 and CHCHD10-what distinguishes the two?

Ikeda Aya A Imai Yuzuru Y Hattori Nobutaka N

Frontiers in cell and developmental biology 20220909

Coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and Coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) are mitochondrial proteins that are thought to be genes which duplicated during evolution and are the causative genes for Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal lobe dementia, respectively. CHCHD2 forms a heterodimer with CHCHD10 and a homodimer with itself, both of which work together within the mitochondria. Various pathogenic and ...[more]

PMID: 36158221

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Project description:The Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (Kii 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 patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's Disease (PD). Distinctly, post-mortem examinations of the brains of affected individuals have shown concurrent hallmarks: the presence of α-synuclein aggregates, which are a signature of PD, and TDP-43, associated with classical ALS. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of Kii ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has cast a spotlight on astrocytes, cells pivotal for maintaining brain health. These astrocytes are likely to play a significant role in the pathogenesis of Kii ALS/PDC. Leveraging advanced iPSC technology, our team cultivated multiple astrocyte lines to probe the disease further. CHCHD2 emerged as asignificantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also unveiled imbalances in specific pathways: those associated with astrocytic cilium dysfunction, known to have ties with 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 a patient’s spinal cord. In sum, our findings suggest a potential compromise 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.

Dataset Information

Neurodegeneration-associated mitochondrial proteins, CHCHD2 and CHCHD10-what distinguishes the two?

Publications

Neurodegeneration-associated mitochondrial proteins, CHCHD2 and CHCHD10-what distinguishes the two?

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