Abstract
Parkinson's disease (PD) is a frequent progressive neurodegenerative disorder. Impaired mitochondrial function is a major feature of sporadic PD. Some susceptibility or causative genes detected in PD are strongly associated with mitochondrial dysfunction including PGC1α, TFAM and GSK3β. microRNAs (miRNAs) are non‐coding RNAs whose altered levels are proven in disparate PD models and human brains. Therefore, the aim of this study was to detect modulations of miRs upstream of PGC1α, TFAM and GSK3β in association with PD onset and progress. In this study, a total of 33 PD subjects and 25 healthy volunteers were recruited. Candidate miRNA (miR‐376a) was selected through target prediction tools and literature survey. Chronic and acute in vitro PD models were created by MPP+‐intoxicated SHSY5Y cells. The levels of miR‐376a and aforementioned genes were assessed by RT‐qPCR. The expression of target genes was decreased in chronic model while there were dramatically up‐regulated levels of those genes in acute model of PD. miR‐376a was strongly altered in both acute and chronic PD models as well as PBMCs of PD patients. Our results also showed overexpression of PGC1α, and TFAM in PBMCs is inversely correlated with down‐regulation of miR‐376a, suggesting that miR‐376a possibly has an impact on PD pathogenesis through regulation of these genes which are involved in mitochondrial function. miR‐376a expression in PD‐derived PBMCs was also correlated with disease severity and may serve as a potential biomarker for PD diagnosis. This is the first study showing altered levels of miR‐376a in PD models and PBMCs, suggesting the probable role of this miRNA in PD pathogenesis. The present study also proposed TFAM and PGC1α as target genes of miR‐376a for the first time, through which it possibly can exert its impact on PD pathogenesis.
Highlights
Parkinson's disease (PD) is the second most frequent neurodegenerative disorder (NDD) whose pathological characteristics are progressive loss of dopaminergic neurons of midbrain and presence of intraneuronal cytoplasmic inclusions, namely “Lewy bodies”.1,2 Around 95% of PD cases are sporadic and familial forms constitute the remainder.[3]
Some susceptibility or causative genes detected in PD are strongly associated with mitochondrial dysfunction including PGC1α, TFAM and GSK3β. microRNAs are non-coding RNAs whose altered levels are proven in disparate PD models and human brains
Our results showed overexpression of PGC1α, and TFAM in peripheral blood mononuclear cells (PBMCs) is inversely correlated with down-regulation of miR-376a, suggesting that miR-376a possibly has an impact on PD pathogenesis through regulation of these genes which are involved in mitochondrial function. miR-376a expression in PD-derived PBMCs was correlated with disease severity and may serve as a potential biomarker for PD diagnosis
Summary
Parkinson's disease (PD) is the second most frequent neurodegenerative disorder (NDD) whose pathological characteristics are progressive loss of dopaminergic neurons of midbrain and presence of intraneuronal cytoplasmic inclusions, namely “Lewy bodies”.1,2 Around 95% of PD cases are sporadic and familial forms constitute the remainder.[3]. Environmental factors as well as genetic susceptibility are decisive factors in sporadic PD aetiology.[9] Beside environmental agents, several susceptibility or causative genes were detected in PD, some of which are strongly associated with mitochondrial dysfunction including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), mitochondrial transcription factor A (TFAM) and glycogen synthase kinase 3 beta (GSK3β).[1] PGC1α is a multifunctional coactivator of transcription factors like NRF-1, NRF-2, TFAM and FOXO receptors, and thereby regulates mitochondrial biogenesis, respiration as well as function.[1,3] since PGC1α induces the expression of several reactive oxygen species (ROS) detoxifying enzymes including SOD1 and 2, catalase and glutathione peroxidase-1, it tightly regulates oxidative capacity and reduces oxidative stress.[3,10] There is a substantial literature indicating possible links between PGC1α and diverse neurodegenerative diseases (NDDs), comprising amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Alzheimer's disease (AD) and PD.[10] As a target gene of PGC1α, TFAM regulates mitochondrial genome replication and transcription as well as mitochondrial biogenesis.[11] TFAM makes a positive contribution to mtDNA stability and initiates synthesis of mtDNA-encoded respiratory chain subunits.[7] GSK3β is widely known for its role in the pathogenesis of a host of neurodegenerative disorders comprising PD, impacting several pathological processes such as neuronal apoptosis, neuroinflammation and dopaminergic (DA) neuron degeneration.[12]. Since maintenance of mitochondrial machinery depends on the action of some mitochondria-related nuclear-encoded proteins,[11] the principal aim of this study was to assess the expression levels PGC1α, TFAM and GSK3β, as well as their predicted upstream miRNA, miR-376a, in chronic and acute models of PD and patient's peripheral blood mononuclear cells (PBMCs)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
