Parkinson's disease: SNCA-, PARK2-, and LRRK2- targeting microRNAs elevated in cingulate gyrus

Tatura, Roman; Kraus, Theo; Giese, Armin; Arzberger, Thomas; Buchholz, Malte; Höglinger, Günter U.; Müller, Ulrich

doi:10.1016/j.parkreldis.2016.09.028

Cited by 71 publications

(52 citation statements)

References 27 publications

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“…Since then, five additional miRNAs, miR-153, miR-34b, miR-34c, miR-214, and miR-1643, were also found to bind to the 3′-UTR of αsynuclein mRNA and inhibit its expression [43][44][45][46]. Among these, miR-7, miR-34b, and miR-34c were shown to be decreased in PD brains [31,37], suggesting that decreased expression of these particular miRNAs in PD brains can result in elevated α-synuclein levels and contribute to PD pathogenesis. Furthermore, we recently found that miR-7 also accelerates the clearance of α-synuclein and its aggregates by promoting autophagy and expedites the degradation of preformed fibrils of α-synuclein endocytosed from outside the cells [47].…”

Section: Pd-causing Genes and Mirnasmentioning

confidence: 99%

“…Identifying miRNAs that are differentially expressed in postmortem brain tissue from PD brains and nonaffected controls helps in understanding the role of miRNAs in the pathogenesis of PD and may lead to recognizing potential therapeutic opportunities. Several studies of this nature have been carried out, and dysregulated miRNAs identified from these studies are listed in Table 2 [30][31][32][33][34][35][36][37]. Initially, profiling miRNAs obtained from the midbrains of PD and control subjects showed that miR-133b is highly enriched in the midbrain but found to be low in PD brains [30].…”

Section: Mirna Profiling Studiesmentioning

confidence: 99%

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Nucleic Acid–Based Therapeutics for Parkinson's Disease

et al. 2019

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Parkinson's disease (PD) is a progressive neurodegenerative disorder that is diagnosed largely on clinical grounds due to characteristic motor manifestations that result from the loss of nigrostriatal dopaminergic neurons. While traditional pharmacological approaches to enhance dopamine levels, such as with L-dopa, can be very effective initially, the chronic use of this dopamine precursor is commonly plagued with motor response complications. Additionally, with advancing disease, non-motor manifestations emerge, including psychosis and dementia that compound patient disability. The pathology includes hallmark intraneuronal inclusions known as Lewy bodies and Lewy neurites that contain fibrillar α-synuclein aggregates. Evidence has also accumulated that these aggregates can propagate across synaptically connected brain regions, a phenomenon that can explain the progressive nature of the disease and the emergence of additional symptoms over time. The level of α-synuclein is believed to play a critical role in its fibrillization and aggregation. Accordingly, nucleic acid-based therapeutics for PD include strategies to deliver dopamine biosynthetic enzymes to boost dopamine production or modulate the basal ganglia circuitry in order to improve motor symptoms. Delivery of trophic factors that might enhance the survival of dopamine neurons is another strategy that has been attempted. These gene therapy approaches utilize viral vectors and are delivered stereotaxically in the brain. Alternative disease-modifying strategies focus on downregulating the expression of the α-synuclein gene using various techniques, including modified antisense oligonucleotides, short hairpin RNA, short interfering RNA, and microRNA. The latter approaches also have implications for dementia with Lewy bodies. Other PD genes can also be targeted using nucleic acids. In this review, we detail these various strategies that are still experimental, and discuss the challenges and opportunities of nucleic acid-based therapeutics for PD.

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Section: Pd-causing Genes and Mirnasmentioning

confidence: 99%

Section: Mirna Profiling Studiesmentioning

confidence: 99%

Nucleic Acid–Based Therapeutics for Parkinson's Disease

et al. 2019

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“…However, in PD patients, none of the EOPD studies showed changes in miR-181a expression whereas in LOPD patients, miR-181a expression was reduced (Table 1 ). Another miRNAs is miR-544 that was increased in the brain tissues of LOPD patients (Tatura et al, 2016 ) and can directly bind to 3′UTR of PARK7 mRNA region to suppress PARK7 expression (Jin et al, 2016 ), however, whether miR-544 is implicated in PD progression remains unknown. Another miRNA is miR-7 that regulates SNCA expression and α-synuclein level (Junn et al, 2009 ; Doxakis, 2013 ).…”

Section: Microrna Regulatory Network In Parkinson Diseasementioning

confidence: 99%

“…In fact, this neuroprotective of miR-7 against α-synuclein aggregates has been replicated in various experimental conditions to induce cell death, including due to impaired mitochondrial activity (Choi et al, 2014 ; Fragkouli and Doxakis, 2014 ) or genetic mutation of A53T in SNCA gene (Fan et al, 2016 ; Zhou et al, 2016 ). Despite these neuroprotective actions of miR-7, only one LOPD study actually showed the differentially expressed miR-7 in human samples (Table 1 ), in which its expression was reduced in LOPD patients at the region of gyri cinguli (Tatura et al, 2016 ). This is particularly important as these findings may imply that miR-7 regulation of α-synuclein is more complicated than the normal direct-mRNA binding and suppression, seen in in vitro cells or experimental animals or it may suggest that miR-7 regulates multiple target genes thus its expression is highly maintained or there are other underlying regulators.…”

Section: Microrna Regulatory Network In Parkinson Diseasementioning

confidence: 99%

MicroRNAs and Target Genes As Biomarkers for the Diagnosis of Early Onset of Parkinson Disease

Arshad

Sulaiman

Saperi

et al. 2017

Front. Mol. Neurosci.

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Among the neurodegenerative disorders, Parkinson's disease (PD) ranks as the second most common disorder with a higher prevalence in individuals aged over 60 years old. Younger individuals may also be affected with PD which is known as early onset PD (EOPD). Despite similarities between the characteristics of EOPD and late onset PD (LODP), EOPD patients experience much longer disease manifestations and poorer quality of life. Although some individuals are more prone to have EOPD due to certain genetic alterations, the molecular mechanisms that differentiate between EOPD and LOPD remains unclear. Recent findings in PD patients revealed that there were differences in the genetic profiles of PD patients compared to healthy controls, as well as between EOPD and LOPD patients. There were variants identified that correlated with the decline of cognitive and motor symptoms as well as non-motor symptoms in PD. There were also specific microRNAs that correlated with PD progression, and since microRNAs have been shown to be involved in the maintenance of neuronal development, mitochondrial dysfunction and oxidative stress, there is a strong possibility that these microRNAs can be potentially used to differentiate between subsets of PD patients. PD is mainly diagnosed at the late stage, when almost majority of the dopaminergic neurons are lost. Therefore, identification of molecular biomarkers for early detection of PD is important. Given that miRNAs are crucial in controlling the gene expression, these regulatory microRNAs and their target genes could be used as biomarkers for early diagnosis of PD. In this article, we discussed the genes involved and their regulatory miRNAs, regarding their roles in PD progression, based on the findings of significantly altered microRNAs in EOPD studies. We also discussed the potential of these miRNAs as molecular biomarkers for early diagnosis.

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“…This holds particular importance for SNCA as different isoforms and expression levels are predicted to affect SNCA aggregation (Bungeroth et al., ; Manda, Yedlapudi, Korukonda, Bojja, & Kalivendi, ). Moreover, the 3′UTR harbors several miR sites, targeted by multiple miRs including miR7 and miR34b,c, shown to affect alpha‐synuclein expression and related phenotypes (Junn et al., ; Kabaria, Choi, Chaudhuri, Mouradian, & Junn, ; McMillan et al., ; Tatura et al., ). Association studies alone have failed to definitively identify all key functional variant(s), because of large haplotype blocks across the gene harboring multiple candidate variants, and significant linkage disequilibrium (LD) in the 3′UTR.…”

Section: Introductionmentioning

confidence: 99%

Alpha‐synuclein mRNA isoform formation and translation affected by polymorphism in the human SNCA 3ʹUTR

Barrie

Lee

Frater

et al. 2018

Molec Gen & Gen Med

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BackgroundMultiple variants in SNCA, encoding alpha‐synuclein, a main component of Lewy bodies, are implicated in Parkinson's disease.MethodsWe searched for cis‐acting SNCA variants using allelic mRNA ratios in human brain tissues. In a SNCA 3′UTR (2,520 bp) luciferase reporter gene assay, translation in SH‐SY5Y cells in the presence of the rs17016074 G/A alleles was measured. To assess clinical impact, we queried neurocognitive genome‐wide association studies.ResultsAllelic ratios deviated up to twofold, measured at a marker SNP in the middle of a long 3′ untranslated region (3′UTR), but not at a marker at its start, suggesting regulation of 3′UTR processing. 3′UTR SNP rs17016074 G/A, minor allele frequency (MAF) <1% in Caucasians, 13% in Africans, strongly associates with large allelic mRNA expression imbalance (AEI), resulting in reduced expression of long 3′UTR isoforms. A second 3′UTR SNP (rs356165) associates with moderate AEI and enhances SNCA mRNA expression. The rs17016074 A allele reduces overall 3′UTR expression in luciferase reporter gene assays but supports more efficient translation, resolving previous contradictory results. We failed to detect significant genome‐wide associations for rs17016074, possibly a result of low MAF in Caucasians or its absence from most genotyping panels. In the “Genome Wide Association Study of Yoruba in Nigeria,” rs356165 was associated with reduced memory performance.ConclusionsHere, we identify two cis‐acting regulatory variants affecting SNCA mRNA expression, measured by allelic ratios in the 3′UTR. The rs17016074 minor A allele is associated with higher expression of luciferase protein activity. Resolving the genetic influence of SNCA polymorphisms requires study of the interactions between multiple regulatory variants with distinct frequencies among populations.

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Parkinson's disease: SNCA-, PARK2-, and LRRK2- targeting microRNAs elevated in cingulate gyrus

Cited by 71 publications

References 27 publications

Nucleic Acid–Based Therapeutics for Parkinson's Disease

Nucleic Acid–Based Therapeutics for Parkinson's Disease

MicroRNAs and Target Genes As Biomarkers for the Diagnosis of Early Onset of Parkinson Disease

Alpha‐synuclein mRNA isoform formation and translation affected by polymorphism in the human SNCA 3ʹUTR

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