Role of miRNAs in Neurodegeneration: From Disease Cause to Tools of Biomarker Discovery and Therapeutics

Abstract

Neurodegenerative diseases originate from neuronal loss in the central nervous system (CNS). These debilitating diseases progress with age and have become common due to an increase in longevity. The National Institute of Environmental Health Science's 2021 annual report suggests around 6.2 million Americans are living with Alzheimer's disease, and there is a possibility that there will be 1.2 million Parkinson's disease patients in the USA by 2030. There is no clear-cut universal mechanism for identifying neurodegenerative diseases, and therefore, they pose a challenge for neurobiology scientists. Genetic and environmental factors modulate these diseases leading to familial or sporadic forms. Prior studies have shown that miRNA levels are altered during the course of the disease, thereby suggesting that these noncoding RNAs may be the contributing factor in neurodegeneration. In this review, we highlight the role of miRNAs in the pathogenesis of neurodegenerative diseases. Through this review, we aim to achieve four main objectives: First, we highlight how dysregulation of miRNA biogenesis led to these diseases. Second, we highlight the computational or bioinformatics tools required to identify the putative molecular targets of miRNAs, leading to biological molecular pathways or mechanisms involved in these diseases. Third, we focus on the dysregulation of miRNAs and their target genes leading to several neurodegenerative diseases. In the final section, we highlight the use of miRNAs as potential diagnostic biomarkers in the early asymptomatic preclinical diagnosis of these age-dependent debilitating diseases. Additionally, we discuss the challenges and advances in the development of miRNA therapeutics for brain targeting. We list some of the innovative strategies employed to deliver miRNA into target cells and the relevance of these viral and non-viral carrier systems in RNA therapy for neurodegenerative diseases. In summary, this review highlights the relevance of studying brain-enriched miRNAs, the mechanisms underlying their regulation of target gene expression, their dysregulation leading to progressive neurodegeneration, and their potential for biomarker marker and therapeutic intervention. This review thereby highlights ways for the effective diagnosis and prevention of these neurodegenerative disorders in the near future.

Keywords: biogenesis; biomarkers and therapeutics; disease mechanisms; miRNAs; neurodegenerative disease.

Figure 1

Schematic diagram showing the various miRNAs and their molecular targets involved in regulating AD [39,40,43,44,45]. These miRNAs modulate the intensity of AD by modulating levels or functions of tau and abeta. Additionally, they modify tau and abeta independent cellular pathways leading to neuronal toxicity.

Figure 2

Schematic diagram depicting various molecular players modulated by miRNAs in PD, HD, and ALS [83,84,96,99,118,139,140]. The miRNA target gene schematic diagram highlights some of the important genes whose levels are post transcriptionally modified miRNAs, leading to alteration of various vital cellular functions of the neurons. This eventually leads to their degeneration.