The Parkinson's disease-related genes act in mitochondrial homeostasis

2012 ◽  
Vol 36 (9) ◽  
pp. 2034-2043 ◽  
Author(s):  
Yan Sai ◽  
Zhongmin Zou ◽  
Kaige Peng ◽  
Zhaojun Dong
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Homeostasis ◽  
Disease Related Genes

scholarly journals PINK1: A Bridge between Mitochondria and Parkinson’s Disease

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 371
Author(s):  
Filipa Barroso Gonçalves ◽  
Vanessa Alexandra Morais
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
High Energy ◽  
Common Denominator ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Homeostasis ◽  
Cellular Environment ◽  
Familial Form ◽  
Mitochondrial Functions

Mitochondria are known as highly dynamic organelles essential for energy production. Intriguingly, in the recent years, mitochondria have revealed the ability to maintain cell homeostasis and ultimately regulate cell fate. This regulation is achieved by evoking mitochondrial quality control pathways that are capable of sensing the overall status of the cellular environment. In a first instance, actions to maintain a robust pool of mitochondria take place; however, if unsuccessful, measures that lead to overall cell death occur. One of the central key players of these mitochondrial quality control pathways is PINK1 (PTEN-induce putative kinase), a mitochondrial targeted kinase. PINK1 is known to interact with several substrates to regulate mitochondrial functions, and not only is responsible for triggering mitochondrial clearance via mitophagy, but also participates in maintenance of mitochondrial functions and homeostasis, under healthy conditions. Moreover, PINK1 has been associated with the familial form of Parkinson’s disease (PD). Growing evidence has strongly linked mitochondrial homeostasis to the central nervous system (CNS), a system that is replenished with high energy demanding long-lasting neuronal cells. Moreover, sporadic cases of PD have also revealed mitochondrial impairments. Thus, one could speculate that mitochondrial homeostasis is the common denominator in these two forms of the disease, and PINK1 may play a central role in maintaining mitochondrial homeostasis. In this review, we will discuss the role of PINK1 in the mitochondrial physiology and scrutinize its role in the cascade of PD pathology.

scholarly journals Chaperone-Mediated Autophagy and Mitochondrial Homeostasis in Parkinson’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-7
Author(s):  
Ruixin Yang ◽  
Guodong Gao ◽  
Zixu Mao ◽  
Qian Yang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Mitochondrial Homeostasis ◽  
New Findings ◽  
Novel Therapeutic Strategies ◽  
Chaperone Mediated Autophagy

Parkinson’s disease (PD), a complex neurodegenerative disorder, is pathologically characterized by the formation of Lewy bodies and loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Mitochondrial dysfunction is considered to be one of the most important causative mechanisms. In addition, dysfunction of chaperone-mediated autophagy (CMA), one of the lysosomal proteolytic pathways, has been shown to play an important role in the pathogenesis of PD. An exciting and important development is recent finding that CMA and mitochondrial quality control may be linked. This review summarizes the studies revealing the link between autophagy and mitochondrial function. Discussions are focused on the connections between CMA and mitochondrial failure and on the role of MEF2D, a neuronal survival factor, in mediating the regulation of mitochondria in the context of CMA. These new findings highlight the need to further explore the possibility of targeting the MEF2D-mitochondria-CMA network in both understanding the PD pathogenesis and developing novel therapeutic strategies.

scholarly journals Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson’s Disease Pathology

2021 ◽  
Vol 13 ◽  
Author(s):  
Anna Wilkaniec ◽  
Anna M. Lenkiewicz ◽  
Lidia Babiec ◽  
Emilia Murawska ◽  
Henryk M. Jęśko ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Fission ◽  
Alpha Synuclein ◽  
Post Translational Modifications ◽  
Protein Levels ◽  
Mitochondrial Homeostasis ◽  
Mitochondrial Superoxide ◽  
Mitochondrial Biosynthesis

Aberrant secretion and accumulation of α-synuclein (α-Syn) as well as the loss of parkin function are associated with the pathogenesis of Parkinson’s disease (PD). Our previous study suggested a functional interaction between those two proteins, showing that the extracellular α-Syn evoked post-translational modifications of parkin, leading to its autoubiquitination and degradation. While parkin plays an important role in mitochondrial biogenesis and turnover, including mitochondrial fission/fusion as well as mitophagy, the involvement of parkin deregulation in α-Syn-induced mitochondrial damage is largely unknown. In the present study, we demonstrated that treatment with exogenous α-Syn triggers mitochondrial dysfunction, reflected by the depolarization of the mitochondrial membrane, elevated synthesis of the mitochondrial superoxide anion, and a decrease in cellular ATP level. At the same time, we observed a protective effect of parkin overexpression on α-Syn-induced mitochondrial dysfunction. α-Syn-dependent disturbances of mitophagy were also shown to be directly related to reduced parkin levels in mitochondria and decreased ubiquitination of mitochondrial proteins. Also, α-Syn impaired mitochondrial biosynthesis due to the parkin-dependent reduction of PGC-1α protein levels. Finally, loss of parkin function as a result of α-Syn treatment induced an overall breakdown of mitochondrial homeostasis that led to the accumulation of abnormal mitochondria. These findings may thus provide the first compelling evidence for the direct association of α-Syn-mediated parkin depletion to impaired mitochondrial function in PD. We suggest that improvement of parkin function may serve as a novel therapeutic strategy to prevent mitochondrial impairment and neurodegeneration in PD (thereby slowing the progression of the disease).

scholarly journals αSynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson’s disease

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Victorio Martin Pozo Devoto ◽  
Nicolas Dimopoulos ◽  
Matías Alloatti ◽  
María Belén Pardi ◽  
Trinidad M. Saez ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Homeostasis

scholarly journals N-semble-based method for identifying Parkinson’s disease genes

2021 ◽  
Author(s):  
Priya Arora ◽  
Ashutosh Mishra ◽  
Avleen Malhi
Keyword(s):  
Neural Network ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gene Prediction ◽  
Gene Identification ◽  
Disease Genes ◽  
Multiple Model ◽  
Machine Learning Methods ◽  
Model Predictions ◽  
Disease Related Genes

AbstractParkinson’s disease (PD) genes identification plays an important role in improving the diagnosis and treatment of the disease. A number of machine learning methods have been proposed to identify disease-related genes, but only few of these methods are adopted for PD. This work puts forth a novel neural network-based ensemble (n-semble) method to identify Parkinson’s disease genes. The artificial neural network is trained in a unique way to ensemble the multiple model predictions. The proposed n-semble method is composed of four parts: (1) protein sequences are used to construct feature vectors using physicochemical properties of amino acid; (2) dimensionality reduction is achieved using the t-Distributed Stochastic Neighbor Embedding (t-SNE) method, (3) the Jaccard method is applied to find likely negative samples from unknown (candidate) genes, and (4) gene prediction is performed with n-semble method. The proposed n-semble method has been compared with Smalter’s, ProDiGe, PUDI and EPU methods using various evaluation metrics. It has been concluded that the proposed n-semble method outperforms the existing gene identification methods over the other methods and achieves significantly higher precision, recall and F Score of 88.9%, 90.9% and 89.8%, respectively. The obtained results confirm the effectiveness and validity of the proposed framework.

scholarly journals Regulation of Mitochondrial Dynamics in Parkinson’s Disease—Is 2-Methoxyestradiol a Missing Piece?

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 248
Author(s):  
Paulina Bastian ◽  
Jaroslaw Dulski ◽  
Anna Roszmann ◽  
Dagmara Jacewicz ◽  
Alicja Kuban-Jankowska ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dynamics ◽  
Point Of View ◽  
Ht22 Cells ◽  
Atp Production ◽  
Mitochondrial Homeostasis ◽  
Multiple Data ◽  
17Β Estradiol ◽  
Oxide Synthase

Mitochondria, as “power house of the cell”, are crucial players in cell pathophysiology. Beyond adenosine triphosphate (ATP) production, they take part in a generation of reactive oxygen species (ROS), regulation of cell signaling and cell death. Dysregulation of mitochondrial dynamics may lead to cancers and neurodegeneration; however, the fusion/fission cycle allows mitochondria to adapt to metabolic needs of the cell. There are multiple data suggesting that disturbed mitochondrial homeostasis can lead to Parkinson’s disease (PD) development. 2-methoxyestradiol (2-ME), metabolite of 17β-estradiol (E2) and potential anticancer agent, was demonstrated to inhibit cell growth of hippocampal HT22 cells by means of nitric oxide synthase (NOS) production and oxidative stress at both pharmacologically and also physiologically relevant concentrations. Moreover, 2-ME was suggested to inhibit mitochondrial biogenesis and to be a dynamic regulator. This review is a comprehensive discussion, from both scientific and clinical point of view, about the influence of 2-ME on mitochondria and its plausible role as a modulator of neuron survival.

scholarly journals Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3022
Author(s):  
Maria Vizziello ◽  
Linda Borellini ◽  
Giulia Franco ◽  
Gianluca Ardolino
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Gene Mutations ◽  
Neuronal Population ◽  
In Vivo Models ◽  
Mitochondrial Homeostasis

The progressive reduction of the dopaminergic neurons of the substantia nigra is the fundamental process underlying Parkinson’s disease (PD), while the mechanism of susceptibility of this specific neuronal population is largely unclear. Disturbances in mitochondrial function have been recognized as one of the main pathways in sporadic PD since the finding of respiratory chain impairment in animal models of PD. Studies on genetic forms of PD have provided new insight on the role of mitochondrial bioenergetics, homeostasis, and autophagy. PINK1 (PTEN-induced putative kinase 1) gene mutations, although rare, are the second most common cause of recessively inherited early-onset PD, after Parkin gene mutations. Our knowledge of PINK1 and Parkin function has increased dramatically in the last years, with the discovery that a process called mitophagy, which plays a key role in the maintenance of mitochondrial health, is mediated by the PINK1/Parkin pathway. In vitro and in vivo models have been developed, supporting the role of PINK1 in synaptic transmission, particularly affecting dopaminergic neurons. It is of paramount importance to further define the role of PINK1 in mitophagy and mitochondrial homeostasis in PD pathogenesis in order to delineate novel therapeutic targets.

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