Abstract
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.
Highlights
Amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) (ALS/PDC) is a unique neurodegenerative disease, with high-incidence foci in Kii Peninsula (Japan), Guam (UnitedAntioxidants 2020, 9, 423; doi:10.3390/antiox9050423 www.mdpi.com/journal/antioxidantsStates), and Western New Guinea (Indonesia) [1]
Clustering analysis and Principal component analysis (PCA) showed that gene expression patterns in Kii ALS/PDC forebrains were different from those in healthy and Alzheimer’s disease (AD) brains, which were examined as a representative tauopathy
We explored genes upstream of the identified analysis showed that the accumulation of disease-specific abnormal proteins (phosphorylated tau, differentially expressed genes in Kii fold) to reveal master regulators and biological processes associated with ALS/PDC, using
Summary
Amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) (ALS/PDC) is a unique neurodegenerative disease, with high-incidence foci in Kii Peninsula (Japan), Guam (UnitedAntioxidants 2020, 9, 423; doi:10.3390/antiox9050423 www.mdpi.com/journal/antioxidantsStates), and Western New Guinea (Indonesia) [1]. Amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) (ALS/PDC) is a unique neurodegenerative disease, with high-incidence foci in Kii Peninsula (Japan), Guam Kii ALS/PDC is a multiple proteinopathy, presenting as a tauopathy similar to Alzheimer’s disease (AD), α-synucleinopathy similar to Parkinson’s disease (PD), and TAR. Theory [7], which are all based on the assumption that environmental factors play an important role in disease development. Genetic factors have been examined [8]. Despite these efforts, the causes of Kii ALS/PDC remain unknown. Since completion of the Human Genome Project, transcriptomics has become a notable research field for the study of human diseases. Transcriptome analysis is a powerful tool that can reveal which RNAs are transcribed by the human genome in specific tissues under different environmental stimuli or specific pathological conditions [9]
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