Noncoding RNAs and Midbrain DA Neurons: Novel Molecular Mechanisms and Therapeutic Targets in Health and Disease

Abstract

Midbrain dopamine neurons have crucial functions in motor and emotional control and their degeneration leads to several neurological dysfunctions such as Parkinson's disease, addiction, depression, schizophrenia, and others. Despite advances in the understanding of specific altered proteins and coding genes, little is known about cumulative changes in the transcriptional landscape of noncoding genes in midbrain dopamine neurons. Noncoding RNAs-specifically microRNAs and long noncoding RNAs-are emerging as crucial post-transcriptional regulators of gene expression in the brain. The identification of noncoding RNA networks underlying all stages of dopamine neuron development and plasticity is an essential step to deeply understand their physiological role and also their involvement in the etiology of dopaminergic diseases. Here, we provide an update about noncoding RNAs involved in dopaminergic development and metabolism, and the related evidence of these biomolecules for applications in potential treatments for dopaminergic neurodegeneration.

Keywords: Parkinson’s disease; RNA therapeutics; direct cell conversion or reprogramming; dopamine neurons; long noncoding RNA; microRNA.

Figure 1

miRNA network involved in DA neuron development. Representative miRNAs involved in the control of self-renewal and proliferation from the neural stem cell (NSC) stage towards dopamine (DA) neuron differentiation. Red arrow-heads or flat-heads indicate positive or negative direct modulation of the indicated genes, respectively. Green arrows indicate overall modulation of a biological process. Dashed lines indicate hypothetical direct or indirect modulation. miRNAs are highlighted by colored boxes.

Figure 2

ncRNA network involved in DA neuron signaling. The picture represents the main microRNA and long noncoding RNAs involved in the regulation of dopamine (DA) neuron signaling, VMAT2 (vesicular monoamine transporter 2), and DAT (dopamine transporter). Red arrow-heads or flat-heads indicate positive or negative direct modulation of the indicated genes, respectively. Green arrows indicate overall modulation of a biological process. Dashed lines indicate hypothetical direct or indirect modulation. ncRNAs are highlighted by colored boxes.

Figure 3

RNA therapeutics approach for neurodegenerative disease. The picture shows an ideal representation of potential RNA therapeutics approaches in which noncoding RNAs (ncRNAs) or antisense oligonucleotides (ASOs) are used to modulate genes involved in neurodegeneration. On the right side of the picture is a potential use of ncRNAs to reprogram and correct patient somatic cells. Red cells indicate diseased cells derived from a neurodegenerative disease patient, whereas green cells represent cells corrected with ncRNAs and reprogrammed towards neural phenotype. On the left side of the picture is a potential direct in vivo reprogramming/correction approach of resident neural cells.