Mitophagy, a Form of Selective Autophagy, Plays an Essential Role in Mitochondrial Dynamics of Parkinson’s Disease

2021 ◽  
Author(s):  
Xiao-Le Wang ◽  
Si-Tong Feng ◽  
Ya-Ting Wang ◽  
Yu-He Yuan ◽  
Zhi-Peng Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Essential Role ◽  
Mitochondrial Dynamics ◽  
Selective Autophagy

scholarly journals TFE3-Mediated Autophagy is Involved in Dopaminergic Neurodegeneration in Parkinson’s Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Xin He ◽  
Yue Xie ◽  
Qiongping Zheng ◽  
Zeyu Zhang ◽  
Shanshan Ma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Transcription Factor ◽  
Dopaminergic Neurons ◽  
Essential Role ◽  
Dopaminergic Neurodegeneration ◽  
Promising Strategy ◽  
Progressive Loss ◽  
Mptp Model

Impairment of autophagy has been strongly implicated in the progressive loss of nigral dopaminergic neurons in Parkinson’s disease (PD). Transcription factor E3 (TFE3), an MiTF/TFE family transcription factor, has been identified as a master regulator of the genes that are associated with lysosomal biogenesis and autophagy. However, whether TFE3 is involved in parkinsonian neurodegeneration remains to be determined. In this study, we found decreased TFE3 expression in the nuclei of the dopaminergic neurons of postmortem human PD brains. Next, we demonstrated that TFE3 knockdown led to autophagy dysfunction and neurodegeneration of dopaminergic neurons in mice, implying that reduction of nuclear TFE3 may contribute to autophagy dysfunction-mediated cell death in PD. Further, we showed that enhancement of autophagy by TFE3 overexpression dramatically reversed autophagy downregulation and dopaminergic neurons loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Taken together, these findings demonstrate that TFE3 plays an essential role in maintaining autophagy and the survival of dopaminergic neurons, suggesting TFE3 activation may serve as a promising strategy for PD therapy.

scholarly journals Reduced Basal Autophagy and Impaired Mitochondrial Dynamics Due to Loss of Parkinson's Disease-Associated Protein DJ-1

PLoS ONE ◽  
2010 ◽  
Vol 5 (2) ◽  
pp. e9367 ◽  
Author(s):  
Guido Krebiehl ◽  
Sabine Ruckerbauer ◽  
Lena F. Burbulla ◽  
Nicole Kieper ◽  
Brigitte Maurer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dynamics

scholarly journals Mitochondrial Dynamics and Mitophagy in the 6-Hydroxydopamine Preclinical Model of Parkinson's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Maria F. Galindo ◽  
Maria E. Solesio ◽  
Sandra Atienzar-Aroca ◽  
Maria J. Zamora ◽  
Joaquín Jordán Bueso
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Therapeutic Potential ◽  
Mitochondrial Dynamics ◽  
Second Messengers ◽  
Treatment Strategies ◽  
Preclinical Model ◽  
Molecular Signaling ◽  
Mitochondrial Division

We discuss the participation of mitochondrial dynamics and autophagy in the 6-hydroxidopamine-induced Parkinson’s disease model. The regulation of dynamic mitochondrial processes such as fusion, fission, and mitophagy has been shown to be an important mechanism controlling cellular fate. An imbalance in mitochondrial dynamics may contribute to both familial and sporadic neurodegenerative diseases including Parkinson’s disease. With special attention we address the role of second messengers as the role of reactive oxygen species and the mitochondria as the headquarters of cell death. The role of molecular signaling pathways, for instance, the participation of Dynamin-related protein 1(Drp1), will also be addressed. Furthermore evidence demonstrates the therapeutic potential of small-molecule inhibitors of mitochondrial division in Parkinson’s disease. For instance, pharmacological inhibition of Drp1, through treatment with the mitochondrial division inhibitor-1, results in the abrogation of mitochondrial fission and in a decrease of the number of autophagic cells. Deciphering the signaling cascades that underlie mitophagy triggered by 6-OHDA, as well as the mechanisms that determine the selectivity of this response, will help to better understand this process and may have impact on human treatment strategies of Parkinson’s disease.

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 Disease-causing mutations in Parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy

2010 ◽  
Vol 189 (4) ◽  
pp. 671-679 ◽  
Author(s):  
Joo-Yong Lee ◽  
Yoshito Nagano ◽  
J. Paul Taylor ◽  
Kah Leong Lim ◽  
Tso-Pang Yao
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
Protein Aggregate ◽  
Selective Autophagy ◽  
Ubiquitin Binding ◽  
Microtubule Motor ◽  
Mechanistic Basis ◽  
Dependent Transport ◽  
Familial Parkinson’S Disease

Mutations in parkin, a ubiquitin ligase, cause early-onset familial Parkinson's disease (AR-JP). How parkin suppresses Parkinsonism remains unknown. Parkin was recently shown to promote the clearance of impaired mitochondria by autophagy, termed mitophagy. Here, we show that parkin promotes mitophagy by catalyzing mitochondrial ubiquitination, which in turn recruits ubiquitin-binding autophagic components, HDAC6 and p62, leading to mitochondrial clearance. During the process, juxtanuclear mitochondrial aggregates resembling a protein aggregate-induced aggresome are formed. The formation of these “mito-aggresome” structures requires microtubule motor-dependent transport and is essential for efficient mitophagy. Importantly, we show that AR-JP–causing parkin mutations are defective in supporting mitophagy due to distinct defects at recognition, transportation, or ubiquitination of impaired mitochondria, thereby implicating mitophagy defects in the development of Parkinsonism. Our results show that impaired mitochondria and protein aggregates are processed by common ubiquitin-selective autophagy machinery connected to the aggresomal pathway, thus identifying a mechanistic basis for the prevalence of these toxic entities in Parkinson's disease.

scholarly journals Mitochondrial Dynamics and Parkinson's Disease: Focus on Parkin

2012 ◽  
Vol 16 (9) ◽  
pp. 935-949 ◽  
Author(s):  
Kah-Leong Lim ◽  
Xiao-Hui Ng ◽  
Lim Gui-Yin Grace ◽  
Tso-Pang Yao
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dynamics ◽  
Disease Focus

scholarly journals Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A): Could It Be a Promising Biomarker and Therapeutic Target in Parkinson’s Disease?

2022 ◽  
Author(s):  
Sijia Yin ◽  
Chao Han ◽  
Yun Xia ◽  
Fang Wan ◽  
Junjie Hu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Phosphatase ◽  
Essential Role ◽  
Protein Phosphatase 2A ◽  
Area Under The Curve ◽  
Alpha Synuclein ◽  
Phosphatase 2A ◽  
Induced Aggregation ◽  
Age And Sex

AbstractParkinson’s disease (PD) is an incurable neurodegenerative disease characterized by aggregation of pathological alpha-synuclein (α-syn) and loss of dopaminergic neuron in the substantia nigra. Inhibition of phosphorylation of the α-syn has been shown to mediate alleviation of PD-related pathology. Protein phosphatase 2A (PP2A), an important serine/threonine phosphatase, plays an essential role in catalyzing dephosphorylation of the α-syn. Here, we identified and validated cancerous inhibitor of PP2A (CIP2A), as a potential diagnostic biomarker for PD. Our data showed that plasma CIP2A concentrations in PD patients were significantly lower compared to age- and sex-matched controls, 1.721 (1.435–2.428) ng/ml vs 3.051(2.36–5.475) ng/ml, p < 0.0001. The area under the curve of the plasma CIP2A in distinguishing PD from the age- and sex-matched controls was 0.776. In addition, we evaluated the role of CIP2A in PD-related pathogenesis in PD cellular and MPTP-induced mouse model. The results demonstrated that CIP2A is upregulated in PD cellular and MPTP-induced mouse models. Besides, suppression of the CIP2A expression alleviates rotenone induced aggregation of the α-syn as well as phosphorylation of the α-syn in SH-SY5Y cells, which is associated with increased PP2A activity. Taken together, our data demonstrated that CIP2A plays an essential role in the mechanisms related to PD development and might be a novel PD biomarker.

scholarly journals Intracellular and Intercellular Mitochondrial Dynamics in Parkinson’s Disease

2019 ◽  
Vol 13 ◽  
Author(s):  
Dario Valdinocci ◽  
Rui F. Simões ◽  
Jaromira Kovarova ◽  
Teresa Cunha-Oliveira ◽  
Jiri Neuzil ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dynamics

scholarly journals Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

2018 ◽  
Vol 46 (4) ◽  
pp. 891-909 ◽  
Author(s):  
Ruby Macdonald ◽  
Katy Barnes ◽  
Christopher Hastings ◽  
Heather Mortiboys
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Therapeutic Target ◽  
Mitochondrial Dynamics ◽  
Central Mechanism ◽  
Phenotypic Screening ◽  
Mitochondrial Abnormalities

Mitochondrial abnormalities have been identified as a central mechanism in multiple neurodegenerative diseases and, therefore, the mitochondria have been explored as a therapeutic target. This review will focus on the evidence for mitochondrial abnormalities in the two most common neurodegenerative diseases, Parkinson's disease and Alzheimer's disease. In addition, we discuss the main strategies which have been explored in these diseases to target the mitochondria for therapeutic purposes, focusing on mitochondrially targeted antioxidants, peptides, modulators of mitochondrial dynamics and phenotypic screening outcomes.

Sign in / Sign up

Export Citation Format

Share Document