MicroRNA profiling of Parkinson's disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function

Abstract

MicroRNAs (miRNAs) are post-transcriptional gene expression regulators, playing key roles in neuronal development, plasticity and disease. Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the presence of protein inclusions or Lewy bodies and a progressive loss of dopaminergic neurons in the midbrain. Here, we have evaluated miRNA expression deregulation in PD brain samples. MiRNA expression profiling revealed decreased expression of miR-34b and miR-34c in brain areas with variable neuropathological affectation at clinical (motor) stages (Braak stages 4 and 5) of the disease, including the amygdala, frontal cortex, substantia nigra and cerebellum. Furthermore, misregulation of miR-34b/c was detected in pre-motor stages (stages 1-3) of the disease, and thus in cases that did not receive any PD-related treatment during life. Depletion of miR-34b or miR-34c in differentiated SH-SY5Y dopaminergic neuronal cells resulted in a moderate reduction in cell viability that was accompanied by altered mitochondrial function and dynamics, oxidative stress and reduction in total cellular adenosin triphosphate content. MiR-34b/c downregulation was coupled to a decrease in the expression of DJ1 and Parkin, two proteins associated to familial forms of PD that also have a role in idiopathic cases. Accordingly, DJ1 and Parkin expression was reduced in PD brain samples displaying strong miR-34b/c downregulation. We propose that early deregulation of miR-34b/c in PD triggers downstream transcriptome alterations underlying mitochondrial dysfunction and oxidative stress, which ultimately compromise cell viability. A better understanding of the cellular pathways controlling and/or controlled by miR-34b/c should allow identification of targets for development of therapeutic approaches.

Loss of MicroRNA-7 Regulation Leads to α-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo

“…49 MiR-34b/c has also been predicted to target the 3'-UTR of the SNCA gene and has been coupled to a decrease in the expression of DJ1 and Parkin, two proteins found to be important in familial forms of PD. 28,50 In addition, miR-205 has been shown to regulate Leucine-rich repeat kinase (LRRK2) another protein linked to sporadic and familial forms of PD. 51 MiR-34b/c and miR-205 also have decreased expression in patients with PD further suggesting an important role for miRs in the pathology of PD.…”

“…Aberrant miR activity has been associated with a number of neurodegenerative diseases including PD. [25][26][27][28] In particular, miR-7 has been shown to bind to the 3'UTR of the SNCA gene and inhibit its translation. 29,30 However, the pathophysiological relevance of the miR-7 targeting of SNCA to PD remains unclear.…”

Circulating microRNA signature of genotype‐by‐age interactions in the long‐lived Ames dwarf mouse

“…Pattern C miRNAs seem to contribute to the df/df mouse longevity by a CR‐independent mechanism. Recent reports demonstrate tumor suppressor (Wu et al ., 2013) and neuroprotective (Minones‐Moyano et al ., 2011) functions for these miRNAs. Wu and colleagues found downregulation of miR‐34c‐3p/5p in glioma tissue.…”

“…MAPK signaling pathways are well known to play important roles in cancer and sensing/transducing stress signals. A neuroprotective role was also suggested for miR‐34b/c because they were broadly downregulated in Parkinson's disease brains, occurring early in the course of the disease and underlying mitochondrial dysfunction and oxidative stress (Minones‐Moyano et al ., 2011). Our functional analysis of pattern C miRNA‐overtargeted genes uncovered enrichment for several neurodevelopmental and synaptic signaling‐related biological processes (Table S4).…”

Epigenetic Landscape of Parkinson's Disease: Emerging Role in Disease Mechanisms and Therapeutic Modalities

“…In particular, the downregulation of miR-34b/c was detected in premotor stages (stages 1-3) of the disease, such that these subjects did not receive any PD-related treatment during life. Additionally, miR-34b/c downregulation was coupled to a decrease in the expression of mitochondria-associated and familial PD-linked proteins DJ-1 and parkin [56]. These findings provide an intriguing connection between mitochondrial dysfunction and the genetic mechanisms of epigenetic regulation in PD pathogenesis.…”