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

• Main Authors: Satoru Morimoto (Author), Mitsuru Ishikawa (Author), Hirotaka Watanabe (Author), Miho Isoda (Author), Masaki Takao (Author), Shiho Nakamura (Author), Fumiko Ozawa (Author), Yoshifumi Hirokawa (Author), Shigeki Kuzuhara (Author), Hideyuki Okano (Author), Yasumasa Kokubo (Author)
• Format: Book
• Published: MDPI AG, 2020-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antiox9050423; 2076-3921
• Keywords: amyotrophic lateral sclerosis (ALS); parkinsonism-dementia complex (PDC); Kii peninsula; transcriptome analysis; stress-responsive proteins; heat shock proteins; Therapeutics. Pharmacology; RM1-950
• Source: Antioxidants, Vol 9, Iss 5, p 423 (2020)

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.