Regulation of Parkin expression as the key balance between neural survival and cancer cell death

Murillo-González, F.E.; García-Aguilar, Rosario; Vega, Libia; Elizondo, Guillermo

doi:10.1016/j.bcp.2021.114650

Cited by 15 publications

(5 citation statements)

References 147 publications

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“…Significant changes in mitochondrial dynamics and organization, such as being elongated, enlarged and over fusion, also occur in different models of cellular senescence (31). Furthermore, it was shown that PRKN (parkin RBR E3 ubiquitin protein ligase) plays a key role in mitochondrial autophagy regulation and neuroprotection (32) and its overexpression inhibits extracellular mitochondrial release under basal and stress conditions (33). In the early and middle stages of AD, Parkin levels increased significantly and the recruitment to depolarized mitochondria increased, promoting mitochondrial autophagy and clearance of damaged mitochondria, but with disease progression, Parkin levels gradually decreased and eventually depleted, which caused a large accumulation of defective mitochondria and eventually affected neuronal function, leading to their death (34).…”

Section: Discussionmentioning

confidence: 99%

PTPRG activates m6A methyltransferase VIRMA to block mitochondrial autophagy mediated neuronal death in Alzheimer’s disease

Luo

Huang

et al. 2022

Preprint

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In Alzheimer's disease (AD), neuronal death is one of the key pathology. However, the initiation of neuronal death in AD is far from clear, and new targets are urgently needed to develop effective therapeutic methods. This study analyzed sequencing data from single-cell RNAseq and spatialomics, and revealed the impact of global single-cell mapping and cell spatial distribution relationships in early stage of AD. We found that microglia subpopulation Mic_PTPRG can anchor neurons based on ligand-receptor interaction pairs and cause ectopic expression of PTPRG in neurons during AD progression. PTPRG in neurons can bind and upregulate VIRMA expression, which in turn increases the level of m6A methylation, enhances PRKN transcript degradation and represses translation. Repressed PRKN expression blocks the clearance of damaged mitochondria in neurons, which in turn reprograms neuronal energy and nutrient metabolic pathways and leads to neuronal death during AD progression. This study elucidates novel mechanisms, by which the PTPRG-dependent microglia-synaptic modification may play a role in AD, providing a new scientific basis for potential therapeutic targets for AD.

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Section: Discussionmentioning

confidence: 99%

PTPRG activates m6A methyltransferase VIRMA to block mitochondrial autophagy mediated neuronal death in Alzheimer’s disease

Luo

Huang

et al. 2022

Preprint

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“…Enhancer chromatin in various subregions in the last three introns of PRKN as well as the SkM/heart-specific enhancer chromatin immediately downstream of the TSS ( Figure 6 and Figure S5 ) might be critical not only for tissue/cell type-specific differences in expression of this gene, but also for its responses to alterations in cell or tissue physiology. These findings are of clinical interest in view of evidence for PRKN dysregulation contributing to idiopathic Parkinson’s disease and other neurological diseases [ 79 ].…”

Section: Discussionmentioning

confidence: 99%

Epigenetics of Mitochondria-Associated Genes in Striated Muscle

2021

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Striated muscle has especially large energy demands. We identified 97 genes preferentially expressed in skeletal muscle and heart, but not in aorta, and found significant enrichment for mitochondrial associations among them. We compared the epigenomic and transcriptomic profiles of the 27 genes associated with striated muscle and mitochondria. Many showed strong correlations between their tissue-specific transcription levels, and their tissue-specific promoter, enhancer, or open chromatin as well as their DNA hypomethylation. Their striated muscle-specific enhancer chromatin was inside, upstream, or downstream of the gene, throughout much of the gene as a super-enhancer (CKMT2, SLC25A4, and ACO2), or even overlapping a neighboring gene (COX6A2, COX7A1, and COQ10A). Surprisingly, the 3′ end of the 1.38 Mb PRKN (PARK2) gene (involved in mitophagy and linked to juvenile Parkinson’s disease) displayed skeletal muscle/myoblast-specific enhancer chromatin, a myoblast-specific antisense RNA, as well as brain-specific enhancer chromatin. We also found novel tissue-specific RNAs in brain and embryonic stem cells within PPARGC1A (PGC-1α), which encodes a master transcriptional coregulator for mitochondrial formation and metabolism. The tissue specificity of this gene’s four alternative promoters, including a muscle-associated promoter, correlated with nearby enhancer chromatin and open chromatin. Our in-depth epigenetic examination of these genes revealed previously undescribed tissue-specific enhancer chromatin, intragenic promoters, regions of DNA hypomethylation, and intragenic noncoding RNAs that give new insights into transcription control for this medically important set of genes.

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“…With a genomic sequence above 1.38 Mb, the PRKN gene is the second largest in the human genome widely expressed in the brain [ 106 ]. More than 170 PRKN mutations have been associated with PD, including point mutations and genomic rearrangements [ 70 ].…”

Section: Dysregulation Of Genes Involved In Recessive Forms Of Pdmentioning

confidence: 99%

Does the Expression and Epigenetics of Genes Involved in Monogenic Forms of Parkinson’s Disease Influence Sporadic Forms?

Lanore

Lesage

Mariani

et al. 2022

Genes

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Parkinson’s disease (PD) is a disorder characterized by a triad of motor symptoms (akinesia, rigidity, resting tremor) related to loss of dopaminergic neurons mainly in the Substantia nigra pars compacta. Diagnosis is often made after a substantial loss of neurons has already occurred, and while dopamine replacement therapies improve symptoms, they do not modify the course of the disease. Although some biological mechanisms involved in the disease have been identified, such as oxidative stress and accumulation of misfolded proteins, they do not explain entirely PD pathophysiology, and a need for a better understanding remains. Neurodegenerative diseases, including PD, appear to be the result of complex interactions between genetic and environmental factors. The latter can alter gene expression by causing epigenetic changes, such as DNA methylation, post-translational modification of histones and non-coding RNAs. Regulation of genes responsible for monogenic forms of PD may be involved in sporadic PD. This review will focus on the epigenetic mechanisms regulating their expression, since these are the genes for which we currently have the most information available. Despite technical challenges, epigenetic epidemiology offers new insights on revealing altered biological pathways and identifying predictive biomarkers for the onset and progression of PD.

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Regulation of Parkin expression as the key balance between neural survival and cancer cell death

Cited by 15 publications

References 147 publications

PTPRG activates m6A methyltransferase VIRMA to block mitochondrial autophagy mediated neuronal death in Alzheimer’s disease

PTPRG activates m6A methyltransferase VIRMA to block mitochondrial autophagy mediated neuronal death in Alzheimer’s disease

Epigenetics of Mitochondria-Associated Genes in Striated Muscle

Does the Expression and Epigenetics of Genes Involved in Monogenic Forms of Parkinson’s Disease Influence Sporadic Forms?

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