Abstract
MicroRNAs are post-transcriptional regulators of gene expression, crucial for neuronal differentiation, survival, and activity. Age-related dysregulation of microRNA biogenesis increases neuronal vulnerability to cellular stress and may contribute to the development and progression of neurodegenerative diseases. All major neurodegenerative disorders are also associated with oxidative stress, which is widely recognized as a potential target for protective therapies. Albeit often considered separately, microRNA networks and oxidative stress are inextricably entwined in neurodegenerative processes. Oxidative stress affects expression levels of multiple microRNAs and, conversely, microRNAs regulate many genes involved in an oxidative stress response. Both oxidative stress and microRNA regulatory networks also influence other processes linked to neurodegeneration, such as mitochondrial dysfunction, deregulation of proteostasis, and increased neuroinflammation, which ultimately lead to neuronal death. Modulating the levels of a relatively small number of microRNAs may therefore alleviate pathological oxidative damage and have neuroprotective activity. Here, we review the role of individual microRNAs in oxidative stress and related pathways in four neurodegenerative conditions: Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD) disease, and amyotrophic lateral sclerosis (ALS). We also discuss the problems associated with the use of oversimplified cellular models and highlight perspectives of studying microRNA regulation and oxidative stress in human stem cell-derived neurons.
Highlights
Neurodegenerative diseases, such as Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD) disease, and Amyotrophic Lateral Sclerosis (ALS), are devastating and currently incurable conditions causing severe cognitive and/or motor impairments predominantly in aged people [1,2]
We explore the concept of targeting specific microRNAs regulating or regulated by these pathways as a strategy to protect neurons in neurodegenerative diseases
Upregulation of mir-4639-5p, targeting DJ-1 expression, increases oxidative stress and causes cell death in SH-SY5Y cells, a frequently used dopamine neuron-like model, and its increased expression was reported in Parkinson’s disease (PD) patients [117]
Summary
Neurodegenerative diseases, such as Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD) disease, and Amyotrophic Lateral Sclerosis (ALS), are devastating and currently incurable conditions causing severe cognitive and/or motor impairments predominantly in aged people [1,2]. Reactive oxygen species (ROS) cause oxidative damage to proteins, lipids, and nucleic acids, compromising critical cellular functions and activating cell death pathways [13]. Oxidative stress and oxidative damage are commonly observed in different neurodegenerative diseases and, therapies aiming to reduce cellular ROS levels may offer neuroprotective treatments for multiple neurodegenerative conditions. Age and disease-related downregulation of the microRNA biogenesis pathway in adult neurons can lead to changes in their survival, functions, and connectivity. Inhibition of Dicer activity and resulting changes in microRNA expression levels have been observed in aging and in neurological and neurodegenerative diseases [30,42,43,44,45,46,47,48,49,50]. Modulating the levels of a relatively small number of microRNAs which regulate the oxidative stress response in neurons may alleviate pathological oxidative damage and have neuroprotective activity. We review the current literature addressing the interplay between oxidative stress and microRNAs in major neurodegenerative diseases
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