Dysregulated miRNAs as Biomarkers and Therapeutical Targets in Neurodegenerative Diseases

Abstract

Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are representative neurodegenerative diseases (NDs) characterized by degeneration of selective neurons, as well as the lack of effective biomarkers and therapeutic treatments. In the last decade, microRNAs (miRNAs) have gained considerable interest in diagnostics and therapy of NDs, owing to their aberrant expression and their ability to target multiple molecules and pathways. Here, we provide an overview of dysregulated miRNAs in fluids (blood or cerebrospinal fluid) and nervous tissue of AD, PD, and ALS patients. By emphasizing those that are commonly dysregulated in these NDs, we highlight their potential role as biomarkers or therapeutical targets and describe the use of antisense oligonucleotides as miRNA therapies.

Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease

“…Nevertheless, changes in miRNA profiles in human models of AD have been scarcely investigated, and translation to the regulation of miRNAs as a potential therapy is lacking. Therefore, it is highly relevant to accelerate research on brain cells and exosomal miRNAs, mainly those that have been associated with inflammation, a condition associated with AD predisposition, spread and pathology [ 79 , 80 ]. Among the several dysregulated miRNAs, miR-124, miR-125b, miR-146a, miR-155 and miR-21 have been the most highlighted miRNAs in biological fluids and biopsy specimens of people with AD [ 80 , 81 ].…”

The Potential Connection between Molecular Changes and Biomarkers Related to ALS and the Development and Regeneration of CNS

“…Since each miRNA can regulate up to hundreds of mRNA targets, it is possible that the transcriptome alterations detected in ALS patients derive, at least partially, from the disruption of miRNA networks. Indeed, studies using miRNA microarrays or RNA deep sequencing have revealed extensive changes in the expression of more than a hundred miRNAs in ALS [ 18 , 19 , 65 , 66 , 67 , 68 ]; however, the detection of the precise roles of specific miRNAs and/or combinations of miRNAs for the development of disease-specific biomarkers is a focus of current research [ 69 , 70 ]. In current review studies, more commonly detected deregulated miRNAs associated with ALS have been collected and include let-7b, miR-9, miR-16-5p, miR-124a, miR-128, miR-132, miR-133b, miR-143, miR-451, miR-181, miR-183, miR-206, miR-338-3p, and miR-638 [ 18 , 19 , 71 , 72 , 73 ].…”

“…Indeed, studies using miRNA microarrays or RNA deep sequencing have revealed extensive changes in the expression of more than a hundred miRNAs in ALS [ 18 , 19 , 65 , 66 , 67 , 68 ]; however, the detection of the precise roles of specific miRNAs and/or combinations of miRNAs for the development of disease-specific biomarkers is a focus of current research [ 69 , 70 ]. In current review studies, more commonly detected deregulated miRNAs associated with ALS have been collected and include let-7b, miR-9, miR-16-5p, miR-124a, miR-128, miR-132, miR-133b, miR-143, miR-451, miR-181, miR-183, miR-206, miR-338-3p, and miR-638 [ 18 , 19 , 71 , 72 , 73 ]. However, data on miRNAs as biomarkers in ALS are sometimes contradictory and currently still not clear enough for translation into clinical practice.…”

“…Here, we propose a possible connection of ALS with neuroregeneration and aberrant early central nervous system (CNS) development [ 16 , 17 ], where the complex pathophysiology could be orchestrated by several non-coding RNAs that also could present potentially useful biomarkers in ALS prognosis and diagnosis. Moreover, the miRNA and lncRNA molecules known to control the expression of the ALS-related genes of interest have been co-located both in the peripheral blood of ALS patients, as well as in brain and spinal cord tissues [ 18 , 19 ], giving a strong indication of possible involvement and importance in the control of both CNS development and ALS pathophysiology.…”

Deregulation of Plasma microRNA Expression in a TARDBP-ALS Family

“…They are tissue-specific, highly correlated with pathology, and can be isolated and measured with minimal invasiveness when isolated from human biological fluids [ 16 ]. Several studies highlight the role of miRNA in ALS pathology by describing dysregulated miRNAs in various biological fluids (CSF, blood, plasma, and serum) in ALS patients compared to healthy controls [ 17 ]. It has been shown that miRNAs specifically produced in motor neurons are present in the plasma of ALS patients and are correlated with disease severity [ 18 ].…”