scholarly journals Mitochondria and Parkinson’s Disease: Clinical, Molecular, and Translational Aspects

2020 ◽  
pp. 1-16 ◽  
Author(s):  
Max Borsche ◽  
Sandro L. Pereira ◽  
Christine Klein ◽  
Anne Grünewald
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Autosomal Dominant ◽  
Alpha Synuclein ◽  
Therapeutic Approaches ◽  
Polymerase Gamma ◽  
Mitochondrial Toxins ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson’s disease (PD). Initially originating from the observation that mitochondrial toxins cause PD, findings from genetic PD supported a contribution of mitochondrial dysfunction to the disease. Here, proteins encoded by the autosomal recessively inherited PD genes Parkin, PTEN-induced kinase 1 (PINK1), and DJ-1 are involved in mitochondrial pathways. Additional evidence for mitochondrial dysfunction stems from models of autosomal-dominant PD due to mutations in alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2). Moreover, patients harboring alterations in mitochondrial polymerase gamma (POLG) often exhibit signs of parkinsonism. While some molecular studies suggest that mitochondrial dysfunction is a primary event in PD, others speculate that it is the result of impaired mitochondrial clearance. Most recent research even implicated damage-associated molecular patterns released from non-degraded mitochondria in neuroinflammatory processes in PD. Here, we summarize the manifold literature dealing with mitochondria in the context of PD. Moreover, in light of recent advances in the field of personalized medicine, patient stratification according to the degree of mitochondrial impairment followed by mitochondrial enhancement therapy may hold potential for at least a subset of genetic and idiopathic PD cases. Thus, in the second part of this review, we discuss therapeutic approaches targeting mitochondrial dysfunction with the aim to prevent or delay neurodegeneration in PD.

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 Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD

2011 ◽  
Vol 2011 ◽  
pp. 1-20 ◽  
Author(s):  
A. R. Esteves ◽  
D. M. Arduíno ◽  
D. F. F. Silva ◽  
C. R. Oliveira ◽  
S. M. Cardoso
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Neuronal Cell ◽  
Alpha Synuclein ◽  
Vital Role ◽  
Microtubule Network ◽  
The Road ◽  
Species Production ◽  
Alpha Synuclein Aggregation

While the etiology of Parkinson's disease remains largely elusive, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in Parkinson's disease. Mitochondria are remarkably primed to play a vital role in neuronal cell survival since they are key regulators of energy metabolism (as ATP producers), of intracellular calcium homeostasis, of NAD+/NADH ratio, and of endogenous reactive oxygen species production and programmed cell death. In this paper, we focus on mitochondrial dysfunction-mediated alpha-synuclein aggregation. We highlight some of the findings that provide proof of evidence for a mitochondrial metabolism control in Parkinson's disease, namely, mitochondrial regulation of microtubule-dependent cellular traffic and autophagic lysosomal pathway. The knowledge that microtubule alterations may lead to autophagic deficiency and may compromise the cellular degradation mechanisms that culminate in the progressive accumulation of aberrant protein aggregates shields new insights to the way we address Parkinson's disease. In line with this knowledge, an innovative window for new therapeutic strategies aimed to restore microtubule network may be unlocked.

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).

A Comprehensive Study of miRNAs in Parkinson’s Disease: Diagnostics and Therapeutic Approaches

2022 ◽  
Vol 21 ◽  
Author(s):  
Saima Owais ◽  
Yasir Hasan Siddique
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Therapeutic Approaches ◽  
Molecular Events ◽  
Disease Diagnostics ◽  
Therapeutic Molecules ◽  
Comprehensive Study

Abstract: Parkinson’s disease (PD) is the second most debilitating neurodegenerative movement disorder. It is characterized by the presence of fibrillar alpha-synuclein amassed in the neurons, known as Lewy bodies. Certain cellular and molecular events are involved leading to the degeneration of dopaminergic neurons. However, the origin and implication of such events are still uncertain. Nevertheless, the role of microRNAs (miRNAs) as important biomarkers and therapeutic molecules is unquestionable. The most challenging task by far in PD treatment has been its late diagnosis followed by therapeutics. miRNAs are an emerging hope to meet the need of early diagnosis, thereby promising an improved movement symptom and prolonged life of the patients. The continuous efforts in discovering the role of miRNAs could be made possible by the utilisation of various animal models of PD. These models help us to understand insights into the mechanism of the disease. Moreover, miRNAs have been surfaced as therapeutically important molecules with distinct delivery systems enhancing their success rate. This review aims at providing an outline of different miRNAs implicated in either PD-associated gene regulation or involved in therapeutics.

Sign in / Sign up

Export Citation Format

Share Document