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Evidence of a Role for the TRPC Subfamily in Mediating Oxidative Stress in Parkinson's Disease.

ABSTRACT: Parkinson's disease (PD) represents one of the most common multifactorial neurodegenerative disorders affecting the elderly population. It is associated with the aggregation of ?-synuclein protein and the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The disease is mainly represented by motor symptoms, such as resting tremors, postural instability, rigidity, and bradykinesia, that develop slowly over time. Parkinson's disease can also manifest as disturbances in non-motor functions. Although the pathology of PD has not yet been fully understood, it has been suggested that the disruption of the cellular redox status may contribute to cellular oxidative stress and, thus, to cell death. The generation of reactive oxygen species and reactive nitrogen intermediates, as well as the dysfunction of dopamine metabolism, play important roles in the degeneration of dopaminergic neurons. In this context, the transient receptor potential channel canonical (TRPC) sub-family plays an important role in neuronal degeneration. Additionally, PD gene products, including DJ-1, SNCA, UCH-L1, PINK-1, and Parkin, also interfere with mitochondrial function leading to reactive oxygen species production and dopaminergic neuronal vulnerability to oxidative stress. Herein, we discuss the interplay between these various biochemical and molecular events that ultimately lead to dopaminergic signaling disruption, highlighting the recently identified roles of TRPC in PD.

SUBMITTER: Maria-Ferreira D

PROVIDER: S-EPMC7225354 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Evidence of a Role for the TRPC Subfamily in Mediating Oxidative Stress in Parkinson's Disease.

Maria-Ferreira Daniele D de Oliveira Natalia Mulinari Turin NMT da Silva Liziane Cristine Malaquias LCM Fernandes Elizabeth Soares ES

Frontiers in physiology 20200508

Parkinson's disease (PD) represents one of the most common multifactorial neurodegenerative disorders affecting the elderly population. It is associated with the aggregation of α-synuclein protein and the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The disease is mainly represented by motor symptoms, such as resting tremors, postural instability, rigidity, and bradykinesia, that develop slowly over time. Parkinson's disease can also manifest as disturbances i ...[more]

PMID: 32457638

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Project description:BackgroundGenetic aberrations have been identified in nasopharyngeal carcinoma (NPC), however, the underlying mechanism remains elusive. There are increasing evidences that the apoptotic nuclease caspase-activated deoxyribonuclease (CAD) is one of the players leading to translocation in leukemia. Oxidative stress, which has been strongly implicated in carcinogenesis, is a potent apoptotic inducer. Most of the NPC etiological factors are known to induce oxidative stress. Although apoptosis is a cell death process, cells possess the potential to survive apoptosis upon DNA repair. Eventually, the surviving cells may carry rearranged chromosomes. We hypothesized that oxidative stress-induced apoptosis may cause chromosomal breaks mediated by CAD. Upon erroneous DNA repair, cells that survive apoptosis may harbor chromosomal rearrangements contributing to NPC pathogenesis. This study focused on the AF9 gene at 9p22, a common deletion region in NPC. We aimed to propose a possible model for molecular mechanism underlying the chromosomal rearrangements in NPC.ResultsIn the present study, we showed that hydrogen peroxide (H2O2) induced apoptosis in NPC (HK1) and normal nasopharyngeal epithelial (NP69) cells, as evaluated by flow cytometric analyses. Activity of caspases 3/7 was detected in H2O2-treated cells. This activity was inhibited by caspase inhibitor (CI). By nested inverse polymerase chain reaction (IPCR), we demonstrated that oxidative stress-induced apoptosis in HK1 and NP69 cells resulted in cleavages within the breakpoint cluster region (BCR) of the AF9 gene. The gene cleavage frequency detected in the H2O2-treated cells was found to be significantly higher than untreated control. We further found that treatment with CI, which indirectly inhibits CAD, significantly reduced the chromosomal breaks in H2O2-cotreated cells. Intriguingly, a few breakpoints were mapped within the AF9 region that was previously reported to translocate with the mixed lineage leukemia (MLL) gene in acute lymphoblastic leukemia (ALL) patient.ConclusionsIn conclusion, our findings suggested that oxidative stress-induced apoptosis could be one of the mechanisms underlying the chromosomal rearrangements in NPC. CAD may play an important role in chromosomal cleavages mediated by oxidative stress-induced apoptosis. A potential model for oxidative stress-induced apoptosis mediating chromosomal rearrangements in NPC is proposed.

Dataset Information

Evidence of a Role for the TRPC Subfamily in Mediating Oxidative Stress in Parkinson's Disease.

Publications

Evidence of a Role for the TRPC Subfamily in Mediating Oxidative Stress in Parkinson's Disease.

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