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Abstract
Recent progress in the research for underlying mechanisms in neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) has led to the development of potentially effective treatment, and hence increased the need for useful biomarkers that may enable early diagnosis and therapeutic monitoring. The deposition of abnormal proteins is a pathological hallmark of neurodegenerative diseases, including β-amyloid in AD, α-synuclein in PD, and the transactive response DNA/RNA binding protein of 43kDa (TDP-43) in ALS. Furthermore, progression of the disease process accompanies the spreading of abnormal proteins. Extracellular proteins and RNAs, including mRNA, micro RNA, and circular RNA, which are present as a composite of exosomes or other forms, play a role in cell–cell communication, and the role of extracellular molecules in the cell-to-cell spreading of pathological processes in neurodegenerative diseases is now in the spotlight. Therefore, extracellular proteins and RNAs are considered potential biomarkers of neurodegenerative diseases, in particular ALS, in which RNA dysregulation has been shown to be involved in the pathogenesis. Here, we review extracellular proteins and RNAs that have been scrutinized as potential biomarkers of neurodegenerative diseases, and discuss the possibility of extracellular RNAs as diagnostic and therapeutic monitoring biomarkers of sporadic ALS.
Highlights
Neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by the progressive loss of specific functions in the central nervous system (CNS), resulting from structural changes in selective neuronal circuits
We summarize extracellular proteins and RNAs as various types of candidate biomarkers of neurodegenerative diseases—in particular sporadic ALS—and discuss the need for the development of biomarkers based on molecular pathogenesis
Many of the so-far identified ALS-linked genes are involved in RNA processing [28], but only a small proportion of sporadic ALS patients carry any of these mutated genes, including chromosome 9 open reading frame 72 (C9ORF72), fused in sarcoma (FUS), transactive response DNA/RNA binding protein of 43kDa (TDP-43), and ataxin 2 (ATXN2)
Summary
Neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by the progressive loss of specific functions in the central nervous system (CNS), resulting from structural changes in selective neuronal circuits. A large number of pathogenic hypotheses have been proposed, including protein misfolding, excitotoxicity, and oxidative stress [14], the mechanisms underlying motor neuron death in ALS remain elusive, even in familial ALS, and neither disease-modifying treatments nor reliable biomarkers of ALS are currently available [10]. In sporadic ALS, a pathological diagnostic hallmark is the disruption of the nuclear localization of TDP-43 (a nuclear protein involved in regulating RNA processing) and the deposition of cytoplasmic aggregates comprising misfolded abnormal variants of this protein in lower motor neurons [16,17]. With the recent development of mechanism-based optimistic clinical trials, the development of diagnostic biomarkers for early phase ALS and predictive and pharmacodynamic biomarkers is crucial in order to enable the initiation of treatment, before the number of motor neurons decreases to below a level that is required to effectively control skeletal muscles. We discuss the possibility of extracellular RNAs as biomarker candidates based on excitotoxicity, which is a plausible pathogenesis of sporadic ALS
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