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Journal articles on the topic 'PRKN'

Author: Grafiati

Published: 9 March 2023

Last updated: 10 March 2023

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1

Sophocleous, Georgios, Darerca Owen, and Helen R. Mott. "The structure and function of protein kinase C-related kinases (PRKs)." Biochemical Society Transactions 49, no. 1 (February 1, 2021): 217–35. http://dx.doi.org/10.1042/bst20200466.

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The protein kinase C-related kinase (PRK) family of serine/threonine kinases, PRK1, PRK2 and PRK3, are effectors for the Rho family small G proteins. An array of studies have linked these kinases to multiple signalling pathways and physiological roles, but while PRK1 is relatively well-characterized, the entire PRK family remains understudied. Here, we provide a holistic overview of the structure and function of PRKs and describe the molecular events that govern activation and autoregulation of catalytic activity, including phosphorylation, protein interactions and lipid binding. We begin with a structural description of the regulatory and catalytic domains, which facilitates the understanding of their regulation in molecular detail. We then examine their diverse physiological roles in cytoskeletal reorganization, cell adhesion, chromatin remodelling, androgen receptor signalling, cell cycle regulation, the immune response, glucose metabolism and development, highlighting isoform redundancy but also isoform specificity. Finally, we consider the involvement of PRKs in pathologies, including cancer, heart disease and bacterial infections. The abundance of PRK-driven pathologies suggests that these enzymes will be good therapeutic targets and we briefly report some of the progress to date.

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2

Lubbe, Steven J., Bernabe I. Bustos, Jing Hu, Dimitri Krainc, Theresita Joseph, Jason Hehir, Manuela Tan, et al. "Assessing the relationship between monoallelic PRKN mutations and Parkinson’s risk." Human Molecular Genetics 30, no. 1 (January 1, 2021): 78–86. http://dx.doi.org/10.1093/hmg/ddaa273.

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Abstract Biallelic Parkin (PRKN) mutations cause autosomal recessive Parkinson’s disease (PD); however, the role of monoallelic PRKN mutations as a risk factor for PD remains unclear. We investigated the role of single heterozygous PRKN mutations in three large independent case-control cohorts totalling 10 858 PD cases and 8328 controls. Overall, after exclusion of biallelic carriers, single PRKN mutations were more common in PD than controls conferring a >1.5-fold increase in the risk of PD [P-value (P) = 0.035], with meta-analysis (19 574 PD cases and 468 488 controls) confirming increased risk [Odds ratio (OR) = 1.65, P = 3.69E-07]. Carriers were shown to have significantly younger ages at the onset compared with non-carriers (NeuroX: 56.4 vs. 61.4 years; exome: 38.5 vs. 43.1 years). Stratifying by mutation type, we provide preliminary evidence for a more pathogenic risk profile for single PRKN copy number variant (CNV) carriers compared with single nucleotide variant carriers. Studies that did not assess biallelic PRKN mutations or consist of predominantly early-onset cases may be biasing these estimates, and removal of these resulted in a loss of association (OR = 1.23, P = 0.614; n = 4). Importantly, when we looked for additional CNVs in 30% of PD cases with apparent monoallellic PRKN mutations, we found that 44% had biallelic mutations, suggesting that previous estimates may be influenced by cryptic biallelic mutation status. While this study supports the association of single PRKN mutations with PD, it highlights confounding effects; therefore, caution is needed when interpreting current risk estimates. Together, we demonstrate that comprehensive assessment of biallelic mutation status is essential when elucidating PD risk associated with monoallelic PRKN mutations.

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3

Koinuma, Takahiro, Taku Hatano, Koji Kamagata, Christina Andica, Akio Mori, Takashi Ogawa, Haruka Takeshige-Amano, et al. "Diffusion MRI Captures White Matter Microstructure Alterations in PRKN Disease." Journal of Parkinson's Disease 11, no. 3 (August 2, 2021): 1221–35. http://dx.doi.org/10.3233/jpd-202495.

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Background: Although pathological studies usually indicate pure dopaminergic neuronal degeneration in patients with parkin (PRKN) mutations, there is no evidence to date regarding white matter (WM) pathology. A previous diffusion MRI study has revealed WM microstructural alterations caused by systemic oxidative stress in idiopathic Parkinson’s disease (PD), and we found that PRKN patients have systemic oxidative stress in serum biomarker studies. Thus, we hypothesized that PRKN mutations might lead to WM abnormalities. Objective: To investigate whether there are WM microstructural abnormalities in early-onset PD patients with PRKN mutations using diffusion tensor imaging (DTI). Methods: Nine PRKN patients and 15 age- and sex-matched healthy controls were recruited. DTI measures were acquired on a 3T MR scanner using a b value of 1,000 s/mm2 along 32 isotropic diffusion gradients. The DTI measures were compared between groups using tract-based spatial statistics (TBSS) analysis. Correlation analysis was also performed between the DTI parameters and several serum oxidative stress markers obtained in a previously conducted metabolomic analysis. Results: Although the WM volumes were not significantly different, the TBSS analysis revealed a corresponding decrease in fractional anisotropy and an increase in mean diffusivity and radial diffusivity in WM areas, such as the anterior and superior corona radiata and uncinate fasciculus, in PRKN patients compared with controls. Furthermore, 9-hydroxystearate, an oxidative stress marker, and disease duration were positively correlated with several parameters in PRKN patients. Conclusion: This pilot study suggests that WM microstructural impairments occur in PRKN patients and are associated with disease duration and oxidative stress.

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4

Borsche, Max, Inke R. König, Sylvie Delcambre, Simona Petrucci, Alexander Balck, Norbert Brüggemann, Alexander Zimprich, et al. "Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism." Brain 143, no. 10 (October 1, 2020): 3041–51. http://dx.doi.org/10.1093/brain/awaa246.

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Abstract There is increasing evidence for a role of inflammation in Parkinson’s disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson’s disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson’s disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson’s disease patients. These results highlight the potential of IL6 as progression marker in Parkinson’s disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson’s disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson’s disease and Parkinson’s disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson’s disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson’s disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson’s disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson’s disease, at least in this subset of patients.

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5

Di Rita, Anthea, Teresa Maiorino, Krenare Bruqi, Floriana Volpicelli, Gian Carlo Bellenchi, and Flavie Strappazzon. "miR-218 Inhibits Mitochondrial Clearance by Targeting PRKN E3 Ubiquitin Ligase." International Journal of Molecular Sciences 21, no. 1 (January 5, 2020): 355. http://dx.doi.org/10.3390/ijms21010355.

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The selective elimination of dysfunctional mitochondria through mitophagy is crucial for preserving mitochondrial quality and cellular homeostasis. The most described mitophagy pathway is regulated by a positive ubiquitylation feedback loop in which the PINK1 (PTEN induced kinase 1) kinase phosphorylates both ubiquitin and the E3 ubiquitin ligase PRKN (Parkin RBR E3 ubiquitin ligase), also known as PARKIN. This event recruits PRKN to the mitochondria, thus amplifying ubiquitylation signal. Here we report that miR-218 targets PRKN and negatively regulates PINK1/PRKN-mediated mitophagy. Overexpression of miR-218 reduces PRKN mRNA levels, thus also reducing protein content and deregulating the E3 ubiquitin ligase action. In fact, following miR-218 overexpression, mitochondria result less ubiquitylated and the autophagy machinery fails to proceed with correct mitochondrial clearance. Since mitophagy defects are associated with various human diseases, these results qualify miR-218 as a promising therapeutic target for human diseases.

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6

Fan, Kuan, Pengzhi Hu, Chengyuan Song, Xiong Deng, Jie Wen, Yiming Liu, and Hao Deng. "Novel Compound Heterozygous PRKN Variants in a Han-Chinese Family with Early-Onset Parkinson’s Disease." Parkinson's Disease 2019 (December 23, 2019): 1–6. http://dx.doi.org/10.1155/2019/9024894.

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Genetic factors are thought to play an important role in the pathogenesis of Parkinson’s disease (PD), particularly early-onset PD. The PRKN gene is the primary disease-causing gene for early-onset PD. The details of its functions remain unclear. This study identified novel compound heterozygous variants (p.T240K and p.L272R) of the PRKN gene in a Han-Chinese family with early-onset PD. This finding is helpful in the genetic diagnosis of PD and also the functional research of the PRKN gene.

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7

Li, Dunhui, May T. Aung-Htut, Kristin A. Ham, Sue Fletcher, and Steve D. Wilton. "A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson’s Disease Arising from Parkin Mutations." International Journal of Molecular Sciences 21, no. 19 (October 1, 2020): 7282. http://dx.doi.org/10.3390/ijms21197282.

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Parkin-type autosomal recessive juvenile-onset Parkinson’s disease is caused by mutations in the PRKN gene and accounts for 50% of all autosomal recessive Parkinsonism cases. Parkin is a neuroprotective protein that has dual functions as an E3 ligase in the ubiquitin–proteasome system and as a transcriptional repressor of p53. While genomic deletions of PRKN exon 3 disrupt the mRNA reading frame and result in the loss of functional parkin protein, deletions of both exon 3 and 4 maintain the reading frame and are associated with a later onset, milder disease progression, indicating this particular isoform retains some function. Here, we describe in vitro evaluation of antisense oligomers that restore functional parkin expression in cells derived from a Parkinson’s patient carrying a heterozygous PRKN exon 3 deletion, by inducing exon 4 skipping to correct the reading frame. We show that the induced PRKN transcript is translated into a shorter but semi-functional parkin isoform able to be recruited to depolarised mitochondria, and also transcriptionally represses p53 expression. These results support the potential use of antisense oligomers as a disease-modifying treatment for selected pathogenic PRKN mutations.

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8

Palmer, R. H., and P. J. Parker. "Expression, purification and characterization of the ubiquitous protein kinase C-related kinase 1." Biochemical Journal 309, no. 1 (July 1, 1995): 315–20. http://dx.doi.org/10.1042/bj3090315.

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The recently described protein kinase C-related kinase (PRK) family is comprised of at least three members: PRK1, PRK2 and PRK3. Here the expression, purification and characterization of the ubiquitously expressed isoform, PRK1, is described. The enzyme was expressed in COS 7 cells and subsequently purified to apparent homogeneity by sequential column chromatography. The purified PRK1 protein migrates as a single 120 kDa polypeptide on SDS/PAGE. It displays a substrate specificity that in part resembles that of protein kinase C (PKC); however, unlike PKC, it is not activated by any combination of phorbol esters, diacylglycerol and Ca2+. Nevertheless, it can be activated by limited proteolysis, indicating a negative regulatory role for the N-terminal domain(s). PRK1 is also activated by phospholipids. The physiological relevance of this activation is discussed.

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9

Broadway, Benjamin J., Paige K. Boneski, Jenny M. Bredenberg, Ana Kolicheski, Xu Hou, Alexandra I. Soto-Beasley, Owen A. Ross, Wolfdieter Springer, and Fabienne C. Fiesel. "Systematic Functional Analysis of PINK1 and PRKN Coding Variants." Cells 11, no. 15 (August 5, 2022): 2426. http://dx.doi.org/10.3390/cells11152426.

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Loss of either PINK1 or PRKN causes an early onset Parkinson’s disease (PD) phenotype. Functionally, PINK1 and PRKN work together to mediate stress-activated mitochondrial quality control. Upon mitochondrial damage, PINK1, a ubiquitin kinase and PRKN, a ubiquitin ligase, decorate damaged organelles with phosphorylated ubiquitin for sequestration and degradation in lysosomes, a process known as mitophagy. While several genetic mutations are established to result in loss of mitophagy function, many others have not been extensively characterized and are of unknown significance. Here, we analyzed a set of twenty variants, ten in each gene, focusing on understudied variants mostly from the Parkinson’s progressive marker initiative, with sensitive assays to define potential functional deficits. Our results nominate specific rare genetic PINK1 and PRKN variants that cause loss of enzymatic function in line with a potential causative role for PD. Additionally, we identify several variants with intermediate phenotypes and follow up on two of them by gene editing midbrain-derived neuronal precursor cells. Thereof derived isogenic neurons show a stability defect of the rare PINK1 D525N mutation, while the common PINK1 Q115L substitution results in reduced kinase activity. Our strategy to analyze variants with sensitive functional readouts will help aid diagnostics and disease treatment in line with current genomic and therapeutic advances.

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10

Lei, Yuchen, and Daniel J. Klionsky. "New regulators of PRKN-independent mitophagy." Autophagy 18, no. 1 (December 19, 2021): 1–3. http://dx.doi.org/10.1080/15548627.2021.2012867.

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11

Brewer, Kelly, Isabel Nip, Justin Bellizzi, Jessica Costa-Guda, and Andrew Arnold. "Molecular analysis of cyclin D1 modulators PRKN and FBX4 as candidate tumor suppressors in sporadic parathyroid adenomas." Endocrine Connections 10, no. 3 (March 2021): 302–8. http://dx.doi.org/10.1530/ec-21-0055.

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Objective Primary hyperparathyroidism is most often caused by a sporadic single-gland parathyroid adenoma (PTA), a tumor type for which cyclin D1 is the only known and experimentally validated oncoprotein. However, the molecular origins of its frequent overexpression have remained mostly elusive. In this study, we explored a potential tumorigenic mechanism that could increase cyclin D1 stability through a defect in molecules responsible for its degradation. Methods We examined two tumor suppressor genes known to modulate cyclin D1 ubiquitination, PRKN and FBXO4 (FBX4), for evidence of classic two-hit tumor suppressor inactivation within a cohort of 82 PTA cases. We examined the cohort for intragenic inactivating and splice site mutations by Sanger sequencing and for locus-associated loss of heterozygosity (LOH) by microsatellite analysis. Results We identified no evidence of bi-allelic tumor suppressor inactivation of PRKN or FBXO4 via inactivating mutation or splice site perturbation, neither in combination with nor independent of LOH. Among the 82 cases, we encountered previously documented benign single nucleotide polymorphisms (SNPs) in 35 tumors at frequencies similar to those reported in the germlines of the general population. Eight cases exhibited intragenic LOH at the PRKN locus, in some cases extending to cover at least an additional 1.7 Mb of chromosome 6q25-26. FBXO4 was not affected by LOH. Conclusion: The absence of evidence for specific bi-allelic inactivation in PRKN and FBXO4 in this sizeable cohort suggests that these genes only rarely, if ever, serve as classic driver tumor suppressors responsible for the growth of PTAs.

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12

Tan, Manuela M. X., Naveed Malek, Michael A. Lawton, Leon Hubbard, Alan M. Pittman, Theresita Joseph, Jason Hehir, et al. "Genetic analysis of Mendelian mutations in a large UK population-based Parkinson’s disease study." Brain 142, no. 9 (July 19, 2019): 2828–44. http://dx.doi.org/10.1093/brain/awz191.

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AbstractOur objective was to define the prevalence and clinical features of genetic Parkinson’s disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson’s Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson’s study, 424 had young-onset Parkinson’s disease (age at onset ≤ 50) and 1799 had late onset Parkinson’s disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 ‘Kompetitive’ allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson’s disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson’s disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors.

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13

Bradshaw, Aaron V., Philip Campbell, Anthony H. V. Schapira, Huw R. Morris, and Jan-Willem Taanman. "The PINK1—Parkin mitophagy signalling pathway is not functional in peripheral blood mononuclear cells." PLOS ONE 16, no. 11 (November 11, 2021): e0259903. http://dx.doi.org/10.1371/journal.pone.0259903.

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Mutations in the PINK1 and PRKN genes are the most common cause of early-onset familial Parkinson disease. These genes code for the PINK1 and Parkin proteins, respectively, which are involved in the degradation of dysfunctional mitochondria through mitophagy. An early step in PINK1 –Parkin mediated mitophagy is the ubiquitination of the mitofusin proteins MFN1 and -2. The ubiquitination of MFN1 and -2 in patient samples may therefore serve as a biomarker to determine the functional effects of PINK1 and PRKN mutations, and to screen idiopathic patients for potential mitophagy defects. We aimed to characterise the expression of the PINK1 –Parkin mitophagy machinery in peripheral blood mononuclear cells (PBMCs) and assess if these cells could serve as a platform to evaluate mitophagy via analysis of MFN1 and -2 ubiquitination. Mitophagy was induced through mitochondrial depolarisation by treatment with the protonophore CCCP and ubiquitinated MFN proteins were analysed by western blotting. In addition, PINK1 and PRKN mRNA and protein expression levels were characterised with reverse transcriptase quantitative PCR and western blotting, respectively. Whilst CCCP treatment led to MFN ubiquitination in primary fibroblasts, SH-SY5Y neuroblastoma cells and Jurkat leukaemic cells, treatment of PBMCs did not induce ubiquitination of MFN. PRKN mRNA and protein was readily detectable in PBMCs at comparable levels to those observed in Jurkat and fibroblast cells. In contrast, PINK1 protein was undetectable and PINK1 mRNA levels were remarkably low in control PBMCs. Our findings suggest that the PINK1 –Parkin mitophagy signalling pathway is not functional in PBMCs. Therefore, PBMCs are not a suitable biosample for analysis of mitophagy function in Parkinson disease patients.

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14

Ghazavi, Farzaneh, Zeinab Fazlali, Setareh Sadat Banihosseini, Sayed-Rzgar Hosseini, Mohammad Hossein Kazemi, Seyedmehdi Shojaee, Khosro Parsa, et al. "PRKN, DJ-1, and PINK1 screening identifies novel splice site mutation in PRKN and two novel DJ-1 mutations." Movement Disorders 26, no. 1 (November 8, 2010): 80–89. http://dx.doi.org/10.1002/mds.23417.

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15

Hutchinson, Catherine L., Peter N. Lowe, Stephen H. McLaughlin, Helen R. Mott, and Darerca Owen. "Differential Binding of RhoA, RhoB, and RhoC to Protein Kinase C-Related Kinase (PRK) Isoforms PRK1, PRK2, and PRK3: PRKs Have the Highest Affinity for RhoB." Biochemistry 52, no. 45 (October 31, 2013): 7999–8011. http://dx.doi.org/10.1021/bi401216w.

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16

Meschede, Jens, Maria Šadić, Nikolas Furthmann, Tim Miedema, Dominik A. Sehr, A. Kathrin Müller-Rischart, Verian Bader, et al. "The parkin-coregulated gene product PACRG promotes TNF signaling by stabilizing LUBAC." Science Signaling 13, no. 617 (February 4, 2020): eaav1256. http://dx.doi.org/10.1126/scisignal.aav1256.

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The Parkin-coregulated gene (PACRG), which encodes a protein of unknown function, shares a bidirectional promoter with Parkin (PRKN), which encodes an E3 ubiquitin ligase. Because PRKN is important in mitochondrial quality control and protection against stress, we tested whether PACRG also affected these pathways in various cultured human cell lines and in mouse embryonic fibroblasts. PACRG did not play a role in mitophagy but did play a role in tumor necrosis factor (TNF) signaling. Similarly to Parkin, PACRG promoted nuclear factor κB (NF-κB) activation in response to TNF. TNF-induced nuclear translocation of the NF-κB subunit p65 and NF-κB–dependent transcription were decreased in PACRG-deficient cells. Defective canonical NF-κB activation in the absence of PACRG was accompanied by a decrease in linear ubiquitylation mediated by the linear ubiquitin chain assembly complex (LUBAC), which is composed of the two E3 ubiquitin ligases HOIP and HOIL-1L and the adaptor protein SHARPIN. Upon TNF stimulation, PACRG was recruited to the activated TNF receptor complex and interacted with LUBAC components. PACRG functionally replaced SHARPIN in this context. In SHARPIN-deficient cells, PACRG prevented LUBAC destabilization, restored HOIP-dependent linear ubiquitylation, and protected cells from TNF-induced apoptosis. This function of PACRG in positively regulating TNF signaling may help to explain the association of PACRG and PRKN polymorphisms with an increased susceptibility to intracellular pathogens.

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17

Santos-Lobato, Bruno L., Artur Schumacher-Schuh, Ignacio F. Mata, Grace H. Letro, Pedro Braga-Neto, Pedro R. P. Brandão, Clécio O. Godeiro-Junior, et al. "Genetics of Parkinson’s disease in Brazil: a systematic review of monogenic forms." Arquivos de Neuro-Psiquiatria 79, no. 7 (July 2021): 612–23. http://dx.doi.org/10.1590/0004-282x-anp-2020-0409.

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ABSTRACT Background: Increasing numbers of mutations causing monogenic forms of Parkinson's disease (PD) have been described, mostly among patients in Europe and North America. Since genetic architecture varies between different populations, studying the specific genetic profile of Brazilian patients is essential for improving genetic counseling and for selecting patients for clinical trials. Objective: We conducted a systematic review to identify genetic studies on Brazilian patients and to set a background for future studies on monogenic forms of PD in Brazil. Methods: We searched MEDLINE, EMBASE and Web of Science from inception to December 2019 using terms for "Parkinson's disease", "genetics" and "Brazil". Two independent reviewers extracted the data. For the genes LRRK2 and PRKN, the estimated prevalence was calculated for each study, and a meta-analysis was performed. Results: A total of 32 studies were included, comprising 94 Brazilian patients with PD with a causative mutation, identified from among 2,872 screened patients (3.2%). PRKN mutations were causative of PD in 48 patients out of 576 (8.3%). LRRK2 mutations were identified in 40 out of 1,556 patients (2.5%), and p.G2019S was the most common mutation (2.2%). Conclusions: PRKN is the most common autosomal recessive cause of PD, and LRRK2 is the most common autosomal dominant form. We observed that there was a lack of robust epidemiological studies on PD genetics in Brazil and, especially, that the diversity of Brazil’s population had not been considered.

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18

Araya, Jun, Kazuya Tsubouchi, Nahoko Sato, Saburo Ito, Shunsuke Minagawa, Hiromichi Hara, Yusuke Hosaka, et al. "PRKN-regulated mitophagy and cellular senescence during COPD pathogenesis." Autophagy 15, no. 3 (October 13, 2018): 510–26. http://dx.doi.org/10.1080/15548627.2018.1532259.

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Ruiz-Lopez, Marta, Maria Eliza Freitas, Lais M. Oliveira, Renato P. Munhoz, Susan H. Fox, Mohammad Rohani, Ekaterina Rogaeva, Anthony E. Lang, and Alfonso Fasano. "Diagnostic delay in Parkinson's disease caused by PRKN mutations." Parkinsonism & Related Disorders 63 (June 2019): 217–20. http://dx.doi.org/10.1016/j.parkreldis.2019.01.010.

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20

Rusilowicz-Jones, Emma V., Francesco G. Barone, Fernanda Martins Lopes, Elezabeth Stephen, Heather Mortiboys, Sylvie Urbé, and Michael J. Clague. "Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy." Life Science Alliance 5, no. 2 (November 29, 2021): e202101287. http://dx.doi.org/10.26508/lsa.202101287.

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The deubiquitylase USP30 is an actionable target considered for treatment of conditions associated with defects in the PINK1-PRKN pathway leading to mitophagy. We provide a detailed cell biological characterization of a benzosulphonamide molecule, compound 39, that has previously been reported to inhibit USP30 in an in vitro enzymatic assay. The current compound offers increased selectivity over previously described inhibitors. It enhances mitophagy and generates a signature response for USP30 inhibition after mitochondrial depolarization. This includes enhancement of TOMM20 and SYNJ2BP ubiquitylation and phosphoubiquitin accumulation, alongside increased mitophagy. In dopaminergic neurons, generated from Parkinson disease patients carrying loss of function PRKN mutations, compound 39 could significantly restore mitophagy to a level approaching control values. USP30 is located on both mitochondria and peroxisomes and has also been linked to the PINK1-independent pexophagy pathway. Using a fluorescence reporter of pexophagy expressed in U2OS cells, we observe increased pexophagy upon application of compound 39 that recapitulates the previously described effect for USP30 depletion. This provides the first pharmacological intervention with a synthetic molecule to enhance peroxisome turnover.

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Seike, Naohiko, Akio Yokoseki, Ryoko Takeuchi, Kento Saito, Hiroaki Miyahara, Akinori Miyashita, Tetsuhiko Ikeda, et al. "Genetic Variations and Neuropathologic Features of Patients with PRKN Mutations." Movement Disorders 36, no. 7 (February 11, 2021): 1634–43. http://dx.doi.org/10.1002/mds.28521.

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22

Niu, Kaifeng, Hongbo Fang, Zixiang Chen, Yuqi Zhu, Qunsong Tan, Di Wei, Yueyang Li, Adayabalam S. Balajee, and Yongliang Zhao. "USP33 deubiquitinates PRKN/parkin and antagonizes its role in mitophagy." Autophagy 16, no. 4 (August 26, 2019): 724–34. http://dx.doi.org/10.1080/15548627.2019.1656957.

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23

Abu Manneh, Rana, Paraskevi P. Chairta, Ellie Mitsi, Maria A. Loizidou, Andrea N. Georgiou, Yiolanda P. Christou, Marios Pantzaris, Eleni Zamba-Papanicolaou, and Andreas Hadjisavvas. "Genetic Study of Early Onset Parkinson’s Disease in Cyprus." International Journal of Molecular Sciences 23, no. 23 (December 6, 2022): 15369. http://dx.doi.org/10.3390/ijms232315369.

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Parkinson’s Disease (PD) is a multifactorial neurodegenerative disease characterized by motor and non-motor symptoms. The etiology of PD remains unclear. However, several studies have demonstrated the interplay of genetic, epigenetic, and environmental factors in PD. Early-onset PD (EOPD) is a subgroup of PD diagnosed between the ages of 21 and 50. Population genetic studies have demonstrated great genetic variability amongst EOPD patients. Hence, this study aimed to obtain a genetic landscape of EOPD in the Cypriot population. Greek-Cypriot EOPD patients (n = 48) were screened for variants in the six most common EOPD-associated genes (PINK1, PRKN, FBXO7, SNCA, PLA2G6, and DJ-1). This included DNA sequencing and Multiplex ligation-dependent probe amplification (MLPA). One previously described frameshift variant in PINK1 (NM_032409.3:c.889del) was detected in five patients (10.4%)—the largest number to be detected to date. Copy number variations in the PRKN gene were identified in one homozygous and 3 compound heterozygous patients (8.3%). To date, the pathogenic variants identified in this study have explained the PD phenotype for 18.8% of the EOPD cases. The results of this study may contribute to the genetic screening of EOPD in Cyprus.

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Narendra, Derek P., and Julia A. Thayer. "Midbrain on Fire: mtDNA Ignites Neuroinflammation in PRKN ‐P." Movement Disorders 37, no. 7 (July 2022): 1332–34. http://dx.doi.org/10.1002/mds.29073.

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Montenegro-Venegas, Carolina, Anil Annamneedi, Sheila Hoffmann-Conaway, Eckart D. Gundelfinger, and Craig C. Garner. "BSN (bassoon) and PRKN/parkin in concert control presynaptic vesicle autophagy." Autophagy 16, no. 9 (August 10, 2020): 1732–33. http://dx.doi.org/10.1080/15548627.2020.1801259.

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Dekker, M. C. J., J. M. Suleiman, D. Bhwana, W. P. Howlett, S. M. Rashid, R. van Minkelen, and B. C. Hamel. "PRKN-related familial Parkinson's disease: First molecular confirmation from East Africa." Parkinsonism & Related Disorders 73 (April 2020): 14–15. http://dx.doi.org/10.1016/j.parkreldis.2020.02.014.

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Hopfner, Franziska, Stefanie H. Mueller, Silke Szymczak, Olaf Junge, Lukas Tittmann, Sandra May, Katja Lohmann, et al. "Private variants in PRKN are associated with late-onset Parkinson's disease." Parkinsonism & Related Disorders 75 (June 2020): 24–26. http://dx.doi.org/10.1016/j.parkreldis.2020.05.003.

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Dächsel, Justus C., Ignacio F. Mata, Owen A. Ross, Julie P. Taylor, Sarah J. Lincoln, Kelly M. Hinkle, Cecilia Huerta, et al. "Digenic parkinsonism: Investigation of the synergistic effects of PRKN and LRRK2." Neuroscience Letters 410, no. 2 (December 2006): 80–84. http://dx.doi.org/10.1016/j.neulet.2006.06.068.

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Agujetas, V. Roca, E. Barbero-Camps, C. De Dios, and A. Colell. "Mitochondrial cholesterol enrichment affects PINK1-PRKN-mediated mitophagy in Alzheimer's disease." European Neuropsychopharmacology 29 (2019): S452. http://dx.doi.org/10.1016/j.euroneuro.2018.11.678.

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Bravo, Paloma, Hossein Darvish, Abbas Tafakhori, Luis J. Azcona, Amir Hossein Johari, Faezeh Jamali, and Coro Paisán-Ruiz. "Molecular characterization of PRKN structural variations identified through whole-genome sequencing." Molecular Genetics & Genomic Medicine 6, no. 6 (October 16, 2018): 1243–48. http://dx.doi.org/10.1002/mgg3.482.

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Wong, Siaw Cheng, Zhun Foo Tan, Yi-Wen Tay, Wan Chung Law, Azlina Ahmad-Annuar, Ai Huey Tan, and Shen-Yang Lim. "Rare homozygous PRKN exon 7 duplication in a Ibanese patient from Northwestern Borneo with young onset Parkinson’s disease." Neurology Asia 27, no. 2 (June 2022): 515–20. http://dx.doi.org/10.54029/2022frs.

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We describe the clinical features of a Sarawakian man of Ibanese ethnicity with young-onset Parkinson’s disease (PD), who carried a very rare homozygous PRKN exon 7 duplication. Truncal dystonia was a prominent feature on presentation, in addition to classical parkinsonian motor features. This report adds to the very limited literature on monogenic causes of PD in Southeast Asia and specifically the indigenous group in the Borneo region.

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Key, Jana, Nesli Ece Sen, Aleksandar Arsović, Stella Krämer, Robert Hülse, Natasha Nadeem Khan, David Meierhofer, Suzana Gispert, Gabriele Koepf, and Georg Auburger. "Systematic Surveys of Iron Homeostasis Mechanisms Reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence." Cells 9, no. 10 (October 2, 2020): 2229. http://dx.doi.org/10.3390/cells9102229.

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Iron deprivation activates mitophagy and extends lifespan in nematodes. In patients suffering from Parkinson’s disease (PD), PINK1-PRKN mutations via deficient mitophagy trigger iron accumulation and reduce lifespan. To evaluate molecular effects of iron chelator drugs as a potential PD therapy, we assessed fibroblasts by global proteome profiles and targeted transcript analyses. In mouse cells, iron shortage decreased protein abundance for iron-binding nucleotide metabolism enzymes (prominently XDH and ferritin homolog RRM2). It also decreased the expression of factors with a role for nucleotide surveillance, which associate with iron-sulfur-clusters (ISC), and are important for growth and survival. This widespread effect included prominently Nthl1-Ppat-Bdh2, but also mitochondrial Glrx5-Nfu1-Bola1, cytosolic Aco1-Abce1-Tyw5, and nuclear Dna2-Elp3-Pold1-Prim2. Incidentally, upregulated Pink1-Prkn levels explained mitophagy induction, the downregulated expression of Slc25a28 suggested it to function in iron export. The impact of PINK1 mutations in mouse and patient cells was pronounced only after iron overload, causing hyperreactive expression of ribosomal surveillance factor Abce1 and of ferritin, despite ferritin translation being repressed by IRP1. This misregulation might be explained by the deficiency of the ISC-biogenesis factor GLRX5. Our systematic survey suggests mitochondrial ISC-biogenesis and post-transcriptional iron regulation to be important in the decision, whether organisms undergo PD pathogenesis or healthy aging.

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Tanaka, Kosuke, Tomoko Yamamori Morita, Yumi Hakozaki, Miyuki Yoshiya, Chiaki Mashima, Jie Liu, Shun-ichiro Kageyama, Akihiro Ohashi, and Susumu Kobayashi. "Abstract 5635: Combined MEK and mitophagy inhibition promotes mtDNA-mediated innate immunity in KRAS-mutant cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5635. http://dx.doi.org/10.1158/1538-7445.am2022-5635.

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Abstract Although mitochondrial DNA (mtDNA) can stimulate innate immune response that potentiates the efficacy of cancer immunotherapy, how to maximize this innate immune system in certain cancer subtypes remains unknown. Here we show that mtDNA is enriched in KRAS-mutant tumor where the dsDNA-sensor machinery cGAS-STING signaling is autonomously activated at the baseline. Intriguingly, MEK inhibitor induces cytosolic mtDNA release to potently activate cGAS-STING pathway, that is counteracted by PRKN-mediated mitophagy to eliminate mtDNA within damaged mitochondria in KRAS-mutant tumor. Combined MEK and mitophagy inhibitors synergistically boost type I IFNs through mitochondrial stress and promote lymphocyte infiltration into the TME in a mtDNA efflux-dependent manner. Moreover, this combination enhances the efficacy of PD-1 blockade in KRAS-mutant tumor. PRKN clinically associates with KRAS/LKB1-mutant subtype, lower antigen-presenting signature, and ICB resistance. Together, targeting mtDNA renders promising strategy to enable cancer immunotherapy in KRAS-mutant cancers. Citation Format: Kosuke Tanaka, Tomoko Yamamori Morita, Yumi Hakozaki, Miyuki Yoshiya, Chiaki Mashima, Jie Liu, Shun-ichiro Kageyama, Akihiro Ohashi, Susumu Kobayashi. Combined MEK and mitophagy inhibition promotes mtDNA-mediated innate immunity in KRAS-mutant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5635.

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Yamano, Koji, and Richard J. Youle. "Two different axes CALCOCO2-RB1CC1 and OPTN-ATG9A initiate PRKN-mediated mitophagy." Autophagy 16, no. 11 (September 7, 2020): 2105–7. http://dx.doi.org/10.1080/15548627.2020.1815457.

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Yu, E., L. Krohn, U. Rudakov, K. Mufti, J. A. Ruskey, F. Asayesh, M. A. Estiar, et al. "Analysis of heterozygous PRKN variants and copy number variations in Parkinson's disease." Parkinsonism & Related Disorders 79 (October 2020): e28. http://dx.doi.org/10.1016/j.parkreldis.2020.06.123.

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Robak, Laurie A., Renqian Du, Bo Yuan, Shen Gu, Isabel Alfradique-Dunham, Vismaya Kondapalli, Evelyn Hinojosa, et al. "Integrated sequencing and array comparative genomic hybridization in familial Parkinson disease." Neurology Genetics 6, no. 5 (July 28, 2020): e498. http://dx.doi.org/10.1212/nxg.0000000000000498.

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ObjectiveTo determine how single nucleotide variants (SNVs) and copy number variants (CNVs) contribute to molecular diagnosis in familial Parkinson disease (PD), we integrated exome sequencing (ES) and genome-wide array-based comparative genomic hybridization (aCGH) and further probed CNV structure to reveal mutational mechanisms.MethodsWe performed ES on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated ES and aCGH data for pathogenic SNVs and CNVs at Mendelian PD gene loci. We confirmed SNVs via Sanger sequencing and further characterized CNVs with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing.ResultsUsing ES, we discovered individuals with known pathogenic SNVs in GBA (p.Glu365Lys, p.Thr408Met, p.Asn409Ser, and p.Leu483Pro) and LRRK2 (p.Arg1441Gly and p.Gly2019Ser). Two subjects were each double heterozygotes for variants in GBA and LRRK2. Based on aCGH, we additionally discovered cases with an SNCA duplication and heterozygous intragenic GBA deletion. Five additional subjects harbored both SNVs (p.Asn52Metfs*29, p.Thr240Met, p.Pro437Leu, and p.Trp453*) and likely disrupting CNVs at the PRKN locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors.ConclusionsIntegrated ES and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PRKN CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.

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Fava, Vinicius M., Yong Zhong Xu, Guillaume Lettre, Nguyen Van Thuc, Marianna Orlova, Vu Hong Thai, Shao Tao, et al. "Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson’s disease." Proceedings of the National Academy of Sciences 116, no. 31 (July 15, 2019): 15616–24. http://dx.doi.org/10.1073/pnas.1901805116.

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Type-1 reactions (T1R) are pathological inflammatory episodes and main contributors to nerve damage in leprosy. Here, we evaluate the genewise enrichment of rare protein-altering variants in 7 genes where common variants were previously associated with T1R. We selected 474 Vietnamese leprosy patients of which 237 were T1R-affected and 237 were T1R-free matched controls. Genewise enrichment of nonsynonymous variants was tested with both kernel-based (sequence kernel association test [SKAT]) and burden methods. Of the 7 genes tested 2 showed statistical evidence of association with T1R. For the LRRK2 gene an enrichment of nonsynonymous variants was observed in T1R-free controls (PSKAT-O = 1.6 × 10−4). This genewise association was driven almost entirely by the gain-of-function variant R1628P (P = 0.004; odds ratio = 0.29). The second genewise association was found for the Parkin coding gene PRKN (formerly PARK2) where 7 rare variants were enriched in T1R-affected cases (PSKAT-O = 7.4 × 10−5). Mutations in both PRKN and LRRK2 are known causes of Parkinson’s disease (PD). Hence, we evaluated to what extent such rare amino acid changes observed in T1R are shared with PD. We observed that amino acids in Parkin targeted by nonsynonymous T1R-risk mutations were also enriched for mutations implicated in PD (P = 1.5 × 10−4). Hence, neuroinflammation in PD and peripheral nerve damage due to inflammation in T1R share overlapping genetic control of pathogenicity.

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Oczkowska, Anna, Wojciech Kozubski, Margarita Lianeri, and Jolanta Dorszewska. "Mutations in PRKN and SNCA Genes Important for the Progress of Parkinson’s Disease." Current Genomics 14, no. 8 (February 2014): 502–17. http://dx.doi.org/10.2174/1389202914666131210205839.

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Oczkowska, Anna, Jolanta Florczak-Wyspianska, Agnieszka Permoda-Osip, Michal Owecki, Margarita Lianeri, Wojciech Kozubski, and Jolanta Dorszewska. "Analysis of PRKN Variants and Clinical Features in Polish Patients with Parkinson’s Disease." Current Genomics 16, no. 4 (June 11, 2015): 215–23. http://dx.doi.org/10.2174/1389202916666150326002549.

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40

Yamada, Tatsuya, Ted M. Dawson, Toru Yanagawa, Miho Iijima, and Hiromi Sesaki. "SQSTM1/p62 promotes mitochondrial ubiquitination independently of PINK1 and PRKN/parkin in mitophagy." Autophagy 15, no. 11 (July 24, 2019): 2012–18. http://dx.doi.org/10.1080/15548627.2019.1643185.

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Pandey, Sanjay, Laxmikant Ramkumarsingh Tomar, Sumeet Kumar, Shreya Dinesh, and B. K. Thelma. "Expanding the canvas of PRKN mutations in familial and early-onset Parkinson disease." Parkinsonism & Related Disorders 66 (September 2019): 216–19. http://dx.doi.org/10.1016/j.parkreldis.2019.08.005.

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Karkheiran, Siamak, Catharine E. Krebs, Hossein Darvish, Mojgan Asadian, Gholam Ali Shahidi, and Coro Paisán-Ruiz. "Variable phenotypic expression in families with early-onset Parkinsonism due to PRKN mutations." Journal of Neurology 261, no. 6 (April 30, 2014): 1223–26. http://dx.doi.org/10.1007/s00415-014-7360-5.

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43

Kim, Deokha, Jinsoo Song, and Eun-Jung Jin. "BNIP3-Dependent Mitophagy via PGC1α Promotes Cartilage Degradation." Cells 10, no. 7 (July 20, 2021): 1839. http://dx.doi.org/10.3390/cells10071839.

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Since mitochondria are suggested to be important regulators in maintaining cartilage homeostasis, turnover of mitochondria through mitochondrial biogenesis and mitochondrial degradation may play an important role in the pathogenesis of osteoarthritis (OA). Here, we found that mitochondrial dysfunction is closely associated with OA pathogenesis and identified the peroxisome proliferator-activated receptor-gamma co-activator 1-alpha (PGC1α) as a potent regulator. The expression level of PGC1α was significantly decreased under OA conditions, and knockdown of PGC1α dramatically elevated the cartilage degradation by upregulating cartilage degrading enzymes and apoptotic cell death. Interestingly, the knockdown of PGC1α activated the parkin RBR E3 ubiquitin protein ligase (PRKN)-independent selective mitochondria autophagy (mitophagy) pathway through the upregulation of BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3). The overexpression of BNIP3 stimulated mitophagy and cartilage degradation by upregulating cartilage-degrading enzymes and chondrocyte death. We identified microRNA (miR)-126-5p as an upstream regulator for PGC1α and confirmed the direct binding between miR-126-5p and 3′ untranslated region (UTR) of PGC1α. An in vivo OA mouse model induced by the destabilization of medial meniscus (DMM) surgery, and the delivery of antago-miR-126 via intra-articular injection significantly decreased cartilage degradation. In sum, the loss of PGC1α in chondrocytes due to upregulation of miR-126-5p during OA pathogenesis resulted in the activation of PRKN-independent mitophagy through the upregulation of BNIP3 and stimulated cartilage degradation and apoptotic death of chondrocytes. Therefore, the regulation of PGC1α:BNIP3 mitophagy axis could be of therapeutic benefit to cartilage-degrading diseases.

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Safiulina, Dzhamilja, Malle Kuum, Vinay Choubey, Miriam A. Hickey, and Allen Kaasik. "Mitochondrial transport proteins RHOT1 and RHOT2 serve as docking sites for PRKN-mediated mitophagy." Autophagy 15, no. 5 (March 4, 2019): 930–31. http://dx.doi.org/10.1080/15548627.2019.1586260.

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Shin, Jung Hwan, Sung-Hye Park, Chaewon Shin, Ji-hoon Kim, Tae Jin Yun, Han-Joon Kim, and Beomseok Jeon. "Negative α-synuclein pathology in the submandibular gland of patients carrying PRKN pathogenic variants." Parkinsonism & Related Disorders 81 (December 2020): 179–82. http://dx.doi.org/10.1016/j.parkreldis.2020.07.004.

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Tang, Chengyuan, Hailong Han, Mingjuan Yan, Shiyao Zhu, Jing Liu, Zhiwen Liu, Liyu He, et al. "PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury." Autophagy 14, no. 5 (February 17, 2018): 880–97. http://dx.doi.org/10.1080/15548627.2017.1405880.

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Kang, Rui, Yangchun Xie, Herbert J. Zeh, Daniel J. Klionsky, and Daolin Tang. "Mitochondrial quality control mediated by PINK1 and PRKN: links to iron metabolism and tumor immunity." Autophagy 15, no. 1 (October 8, 2018): 172–73. http://dx.doi.org/10.1080/15548627.2018.1526611.

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Soutar, Marc P. M., Liam Kempthorne, Emily Annuario, Christin Luft, Selina Wray, Robin Ketteler, Marthe H. R. Ludtmann, and Hélène Plun-Favreau. "FBS/BSA media concentration determines CCCP’s ability to depolarize mitochondria and activate PINK1-PRKN mitophagy." Autophagy 15, no. 11 (May 7, 2019): 2002–11. http://dx.doi.org/10.1080/15548627.2019.1603549.

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Yan, Chaojun, Longlong Gong, Li Chen, Meng Xu, Hussein Abou-Hamdan, Mingliang Tang, Laurent Désaubry, and Zhiyin Song. "PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis." Autophagy 16, no. 3 (June 16, 2019): 419–34. http://dx.doi.org/10.1080/15548627.2019.1628520.

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Okubadejo, Njideka, Angela Britton, Cynthia Crews, Rufus Akinyemi, John Hardy, Andrew Singleton, and Jose Bras. "Analysis of Nigerians with Apparently Sporadic Parkinson Disease for Mutations in LRRK2, PRKN and ATXN3." PLoS ONE 3, no. 10 (October 17, 2008): e3421. http://dx.doi.org/10.1371/journal.pone.0003421.

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