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Synaptopathy in Kii ALS/PDC, a disease concept based on transcriptome analyses of human brains

ABSTRACT: Amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) (ALS/PDC) is a unique endemic neurodegenerative disease, with high-incidence foci in the Kii Peninsula, Japan. Although ALS/PDC presents with multiple proteinopathies, the genetic and environmental factors that influence disease onset remain unknown. We performed transcriptome analyses of patients’ brains, which may provide new insights into the pathomechanisms underlying Kii ALS/PDC. We prepared frozen brains from 3 healthy controls (frontal lobe and temporal lobe), 3 patients with Alzheimer’s disease (AD) (frontal lobe and temporal lobe) as tauopathy-disease controls, and 21 patients with Kii ALS/PDC (frontal lobe and/or temporal lobe). We acquired microarray data from the cerebral gray and white matter tissues of Kii ALS/PDC patients. Microarray data revealed that the expression levels of genes associated with neurons, heat shock proteins (Hsps), DNA binding/damage, and senescence were significantly changed in Kii ALS/PDC brains compared with those in control brains. The RNA expression pattern observed for Kii ALS type brains was similar to that for Kii PDC type brains and unlike those of control and AD brains. Additionally, pathway and network analyses indicated that the molecular pathogenic mechanism underlying Kii ALS/PDC may be associated with the oxidative phosphorylation of mitochondria, ribosomes, and the synaptic vesicle cycle; in particular, upstream regulators of these mechanisms may be found in synapses and during synaptic trafficking. Therefore, we propose the novel disease concept of “synaptopathy” for Kii ALS/PDC. Furthermore, phenotypic differences between Kii ALS type and Kii PDC type were observed, based on the human leukocyte antigen (HLA) haplotype. We performed exhaustive transcriptome analyses of Kii ALS/PDC brains, for the first time, and revealed new insights indicating that Kii ALS/PDC may be a synaptopathy. Determining the relationship between synaptic dysfunction and the pathogenesis of ALS/PDC may provide a new step toward understanding this mysterious disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139384 | GEO | 2019/10/26

REPOSITORIES: GEO

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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.

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Synaptopathy in Kii ALS/PDC, a disease concept based on transcriptome analyses of human brains

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