Brain Transcriptome Analysis Links Deficiencies of Stress-Responsive Proteins to the Pathomechanism of Kii ALS/PDC

Amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC) is a unique endemic neurodegenerative disease, with high-incidence foci in Kii Peninsula, Japan. To gather new insights into the pathological mechanisms underlying Kii ALS/PDC, we performed transcriptome analyses of patient br...

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Bibliographic Details
Published in:Antioxidants 2020-05, Vol.9 (5), p.423
Main Authors: Morimoto, Satoru, Ishikawa, Mitsuru, Watanabe, Hirotaka, Isoda, Miho, Takao, Masaki, Nakamura, Shiho, Ozawa, Fumiko, Hirokawa, Yoshifumi, Kuzuhara, Shigeki, Okano, Hideyuki, Kokubo, Yasumasa
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
amyotrophic lateral sclerosis (ALS)
Dementia
Development and progression
Heat shock proteins
Kii peninsula
Parkinson disease
parkinsonism-dementia complex (PDC)
Physiological aspects
stress-responsive proteins
transcriptome analysis
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Summary:Amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC) is a unique endemic neurodegenerative disease, with high-incidence foci in Kii Peninsula, Japan. To gather new insights into the pathological mechanisms underlying Kii ALS/PDC, we performed transcriptome analyses of patient brains. We prepared frozen brains from three individuals without neurodegenerative diseases, three patients with Alzheimer's disease, and 21 patients with Kii ALS/PDC, and then acquired microarray data from cerebral gray and white matter tissues. Microarray results revealed that expression levels of genes associated with heat shock proteins, DNA binding/damage, and senescence were significantly altered in patients with ALS/PDC compared with healthy individuals. The RNA expression pattern observed for ALS-type brains was similar to that of PDC-type brains. Additionally, pathway and network analyses indicated that the molecular mechanism underlying ALS/PDC may be associated with 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. Furthermore, phenotypic differences between ALS-type and PDC-type were observed, based on HLA haplotypes. In conclusion, determining the relationship between stress-responsive proteins, synaptic dysfunction, and the pathogenesis of ALS/PDC in the Kii peninsula may provide new understanding of this mysterious disease.
ISSN:2076-3921
2076-3921
DOI:10.3390/antiox9050423