Abstract
Parkinson’s disease (PD) is the most prevalent central nervous system (CNS) movement disorder and the second most common neurodegenerative disease overall. PD is characterized by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) within the midbrain, accumulation of alpha-synuclein (α-SYN) in Lewy bodies and neurites and excessive neuroinflammation. The neurodegenerative processes typically begin decades before the appearance of clinical symptoms. Therefore, the diagnosis is achievable only when the majority of the relevant DAergic neurons have already died and for that reason available treatments are only palliative at best. The causes and mechanism(s) of this devastating disease are ill-defined but complex interactions between genetic susceptibility and environmental factors are considered major contributors to the etiology of PD. In addition to the role of classical gene mutations in PD, the importance of regulatory elements modulating gene expression has been increasingly recognized. One example is the critical role played by microRNAs (miRNAs) in the development and homeostasis of distinct populations of neurons within the CNS and, in particular, in the context of PD. Recent reports demonstrate how distinct miRNAs are involved in the regulation of PD genes, whereas profiling approaches are unveiling variations in the abundance of certain miRNAs possibly relevant either to the onset or to the progression of the disease. In this review, we provide an overview of the miRNAs recently found to be implicated in PD etiology, with particular focus on their potential relevance as PD biomarkers, as well as their possible use in PD targeted therapy.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD), affecting approximately 1% of people over 65 years and 5% of those over 85 [1]
While the hemizygous mice showed a marked decrease of DA levels in the striatum without any neuronal loss, the nullizygous mice showed a progressive DAergic neurodegeneration coupled with motoneuronal deficits, demonstrating that level of Dicer expressed was important in determining the severity of the PD-related symptoms [68]
The upregulation of let-7 and miR-184 * attenuated the neurotoxic effects of mutant leucine-rich repeat kinase 2 (LRRK2). These findings suggest that LRRK2 may play a role in PD pathogenesis via miRNA pathway modulation, highlighting new possible therapeutic strategies for PD [106]
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD), affecting approximately 1% of people over 65 years and 5% of those over 85 [1]. Cuellar and colleagues [66] generated a conditional Dicer KO, within DA receptive (DAceptive) striatal neurons, by using a CRE recombinase expressed under the control of DA receptor promoter These mice showed behavioral defects and decreased life span. While the hemizygous mice showed a marked decrease of DA levels in the striatum without any neuronal loss, the nullizygous mice showed a progressive DAergic neurodegeneration coupled with motoneuronal deficits, demonstrating that level of Dicer expressed was important in determining the severity of the PD-related symptoms (see Section 4) [68] Another enzyme involved in miRNA biosynthesis (i.e., DGCR8) was found potentially related to PD. Functional experiments are further needed to directly correlate the PD occurrence with the DGCR8 chromosomal loss [69] (Figure 1)
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