scholarly journals Genetic Mutations and Mitochondrial Toxins Shed New Light on the Pathogenesis of Parkinson's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Shigeto Sato ◽  
Nobutaka Hattori
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Cultured Cells ◽  
Cellular Functions ◽  
Carbonyl Cyanide ◽  
Mitochondrial Toxins ◽  
Cellular Abnormalities ◽  
Mitochondrial Uncoupler

The cellular abnormalities in Parkinson's disease (PD) include mitochondrial dysfunction and oxidative damage, which are probably induced by both genetic predisposition and environmental factors. Mitochondrial dysfunction has long been implicated in the pathogenesis of PD. The recent discovery of genes associated with the etiology of familial PD has emphasized the role of mitochondrial dysfunction in PD. The discovery and increasing knowledge of the function of PINK1 and parkin, which are associated with the mitochondria, have also enhanced the understanding of cellular functions. The PINK1-parkin pathway is associated with quality control of the mitochondria, as determined in cultured cells treated with the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), which causes mitochondrial depolarization. To date, the use of mitochondrial toxins, for example, 1-methyl-4-phynyl-tetrahydropyridine (MPTP) and CCCP, has contributed to our understanding of PD. We review how these toxins and familial PD gene products are associated with and have enhanced our understanding of the role of mitochondrial dysfunction in PD.

scholarly journals Role of MicroRNAs in Parkinson’s Disease

2019 ◽  
Vol 20 (22) ◽  
pp. 5649 ◽  
Author(s):  
Suh Yee Goh ◽  
Yin Xia Chao ◽  
Shaikali Thameem Dheen ◽  
Eng-King Tan ◽  
Samuel Sam-Wah Tay
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Small Sample Size ◽  
Small Sample ◽  
Biological Molecules ◽  
Incomplete Penetrance ◽  
Cellular Functions ◽  
Druggable Targets ◽  
The Brain

Parkinson’s disease (PD) is a disabling neurodegenerative disease that manifests with resting tremor, bradykinesia, rigidity and postural instability. Since the discovery of microRNAs (miRNAs) in 1993, miRNAs have been shown to be important biological molecules involved in diverse processes to maintain normal cellular functions. Over the past decade, many studies have reported dysregulation of miRNA expressions in PD. Here, we identified 15 miRNAs from 34 reported screening studies that demonstrated dysregulation in the brain and/or neuronal models, cerebrospinal fluid (CSF) and blood. Specific miRNAs-of-interest that have been implicated in PD pathogenesis include miR-30, miR-29, let-7, miR-485 and miR-26. However, there are several challenges and limitations in drawing definitive conclusions due to the small sample size in clinical studies, varied laboratory techniques and methodologies and their incomplete penetrance of the blood–brain barrier. Developing an optimal delivery system and unravelling druggable targets of miRNAs in both experimental and human models and clinical validation of the results may pave way for novel therapeutics in PD.

scholarly journals Mitochondrial Fusion/Fission, Transport and Autophagy in Parkinson's Disease: When Mitochondria Get Nasty

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Daniela M. Arduíno ◽  
A. Raquel Esteves ◽  
Sandra M. Cardoso
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Growing Body ◽  
Parkinsonian Disorders ◽  
Mitochondrial Trafficking

Understanding the molecular basis of Parkinson's disease (PD) has proven to be a major challenge in the field of neurodegenerative diseases. Although several hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of PD, a growing body of evidence has highlighted the role of mitochondrial dysfunction and the disruption of the mechanisms of mitochondrial dynamics in PD and other parkinsonian disorders. In this paper, we comment on the recent advances in how changes in the mitochondrial function and mitochondrial dynamics (fusion/fission, transport, and clearance) contribute to neurodegeneration, specifically focusing on PD. We also evaluate the current controversies in those issues and discuss the role of fusion/fission dynamics in the mitochondrial lifecycle and maintenance. We propose that cellular demise and neurodegeneration in PD are due to the interplay between mitochondrial dysfunction, mitochondrial trafficking disruption, and impaired autophagic clearance.

scholarly journals The role of mitochondria-targeted antioxidant MitoQ in neurodegenerative disease

2018 ◽  
pp. 1-8
Author(s):  
Linlin Zhang ◽  
Aurelio Reyes ◽  
Xiangdong Wang
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disease ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
And Oxidative Stress

Abstract: The discovery of charged molecules being able to cross the mitochondrial membrane has prompted many scholars to exploit this idea to find a way of preventing or slowing down aging. In this paper, we will focus on mitochondriatargeted antioxidants, which are cationic derivatives of plastoquinone, and in particular on the mitochondria-targeted antioxidant therapy of neurodegenerative diseases. It is well known that the accumulation of amyloid-β peptide (Aβ) in mitochondria and its related mitochondrial dysfunction are critical signatures of Alzheimer’ s disease (AD). In another neurodegenerative disease, Parkinson’s disease (PD), the loss of dopaminergic neurons in the substantia nigra and the production of Lewy bodies are among their pathological features. Pathogenesis of Parkinson’s disease and Alzheimer’s disease has been frequently linked to mitochondrial dysfunction and oxidative stress. Recent studies show that MitoQ, a mitochondria-targeted antioxidant, may possess therapeutic potential for Aβ-related and oxidative stress-associated neurodegenerative diseases, especially AD. Although MitoQ has been developed to the stage of clinical trials in PD, its true clinical effect still need further verification. This review aims to discuss the role of mitochondrial pathology in neurodegenerative diseases, as well as the recent development of mitochondrial targeted antioxidants as a potential treatment for these diseases by removing excess oxygen free radicals and inhibiting lipid peroxidation in order to improve mitochondrial function.  

scholarly journals Dopamine Oxidation and Autophagy

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Patricia Muñoz ◽  
Sandro Huenchuguala ◽  
Irmgard Paris ◽  
Juan Segura-Aguilar
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Protein Degradation ◽  
Dopaminergic Neurons ◽  
Molecular Mechanisms ◽  
Neurodegenerative Process ◽  
Dopamine Oxidation

The molecular mechanisms involved in the neurodegenerative process of Parkinson's disease remain unclear. Currently, there is a general agreement that mitochondrial dysfunction,α-synuclein aggregation, oxidative stress, neuroinflammation, and impaired protein degradation are involved in the neurodegeneration of dopaminergic neurons containing neuromelanin in Parkinson's disease. Aminochrome has been proposed to play an essential role in the degeneration of dopaminergic neurons containing neuromelanin by inducing mitochondrial dysfunction, oxidative stress, the formation of neurotoxicα-synuclein protofibrils, and impaired protein degradation. Here, we discuss the relationship between the oxidation of dopamine to aminochrome, the precursor of neuromelanin, autophagy dysfunction in dopaminergic neurons containing neuromelanin, and the role of dopamine oxidation to aminochrome in autophagy dysfunction in dopaminergic neurons. Aminochrome induces the following: (i) the formation ofα-synuclein protofibrils that inactivate chaperone-mediated autophagy; (ii) the formation of adducts withα- andβ-tubulin, which induce the aggregation of the microtubules required for the fusion of autophagy vacuoles and lysosomes.

scholarly journals Parkin is recruited selectively to impaired mitochondria and promotes their autophagy

2008 ◽  
Vol 183 (5) ◽  
pp. 795-803 ◽  
Author(s):  
Derek Narendra ◽  
Atsushi Tanaka ◽  
Der-Fen Suen ◽  
Richard J. Youle
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mammalian Cells ◽  
Loss Of Function ◽  
Gene Coding ◽  
Selective Elimination ◽  
Mitochondrial Toxins ◽  
Early Onset Parkinson’S Disease ◽  
Increased Susceptibility

Loss-of-function mutations in Park2, the gene coding for the ubiquitin ligase Parkin, are a significant cause of early onset Parkinson's disease. Although the role of Parkin in neuron maintenance is unknown, recent work has linked Parkin to the regulation of mitochondria. Its loss is associated with swollen mitochondria and muscle degeneration in Drosophila melanogaster, as well as mitochondrial dysfunction and increased susceptibility to mitochondrial toxins in other species. Here, we show that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential in mammalian cells. After recruitment, Parkin mediates the engulfment of mitochondria by autophagosomes and the selective elimination of impaired mitochondria. These results show that Parkin promotes autophagy of damaged mitochondria and implicate a failure to eliminate dysfunctional mitochondria in the pathogenesis of Parkinson's disease.

Use of Cytoplasmic Hybrid Cell Lines for Elucidating the Role of Mitochondrial Dysfunction in Alzheimer's Disease and Parkinson's Disease

1999 ◽  
Vol 893 (1 OXIDATIVE/ENE) ◽  
pp. 176-191 ◽  
Author(s):  
SOUMITRA S. GHOSH ◽  
RUSSELL H. SWERDLOW ◽  
SCOTT W. MILLER ◽  
BRINA SHEEMAN ◽  
W. DAVIS PARKER ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Cell Lines ◽  
Hybrid Cell ◽  
Hybrid Cell Lines

scholarly journals Parkinson’s disease–associated VPS35 mutant reduces mitochondrial membrane potential and impairs PINK1/Parkin-mediated mitophagy

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Kai Yu Ma ◽  
Michiel R. Fokkens ◽  
Fulvio Reggiori ◽  
Muriel Mari ◽  
Dineke S. Verbeek
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Membrane Potential ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Membrane Potential ◽  
Ubiquitin Ligase ◽  
Mitochondrial Membrane ◽  
Mitochondrial Potential ◽  
Carbonyl Cyanide ◽  
Vacuolar Protein

Abstract Background Mitochondrial dysfunction plays a prominent role in the pathogenesis of Parkinson’s disease (PD), and several genes linked to familial PD, including PINK1 (encoding PTEN-induced putative kinase 1 [PINK1]) and PARK2 (encoding the E3 ubiquitin ligase Parkin), are directly involved in processes such as mitophagy that maintain mitochondrial health. The dominant p.D620N variant of vacuolar protein sorting 35 ortholog (VPS35) gene is also associated with familial PD but has not been functionally connected to PINK1 and PARK2. Methods To better mimic and study the patient situation, we used CRISPR-Cas9 to generate heterozygous human SH-SY5Y cells carrying the PD-associated D620N variant of VPS35. These cells were treated with a protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP) to induce the PINK1/Parkin-mediated mitophagy, which was assessed using biochemical and microscopy approaches. Results Mitochondria in the VPS35-D620N cells exhibited reduced mitochondrial membrane potential and appeared to already be damaged at steady state. As a result, the mitochondria of these cells were desensitized to the CCCP-induced collapse in mitochondrial potential, as they displayed altered fragmentation and were unable to accumulate PINK1 at their surface upon this insult. Consequently, Parkin recruitment to the cell surface was inhibited and initiation of the PINK1/Parkin-dependent mitophagy was impaired. Conclusion Our findings extend the pool of evidence that the p.D620N mutation of VPS35 causes mitochondrial dysfunction and suggest a converging pathogenic mechanism among VPS35, PINK1 and Parkin in PD.

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