scholarly journals Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 283
Author(s):  
Daniel Aghaie Madsen ◽  
Sissel Ida Schmidt ◽  
Morten Blaabjerg ◽  
Morten Meyer
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Ubiquitin Proteasome System ◽  
Loss Of Function ◽  
Functional Interaction ◽  
Future Studies ◽  
Ubiquitin Proteasome

Parkin and α-synuclein are two key proteins involved in the pathophysiology of Parkinson’s disease (PD). Neurotoxic alterations of α-synuclein that lead to the formation of toxic oligomers and fibrils contribute to PD through synaptic dysfunction, mitochondrial impairment, defective endoplasmic reticulum and Golgi function, and nuclear dysfunction. In half of the cases, the recessively inherited early-onset PD is caused by loss of function mutations in the PARK2 gene that encodes the E3-ubiquitin ligase, parkin. Parkin is involved in the clearance of misfolded and aggregated proteins by the ubiquitin-proteasome system and regulates mitophagy and mitochondrial biogenesis. PARK2-related PD is generally thought not to be associated with Lewy body formation although it is a neuropathological hallmark of PD. In this review article, we provide an overview of post-mortem neuropathological examinations of PARK2 patients and present the current knowledge of a functional interaction between parkin and α-synuclein in the regulation of protein aggregates including Lewy bodies. Furthermore, we describe prevailing hypotheses about the formation of intracellular micro-aggregates (synuclein inclusions) that might be more likely than Lewy bodies to occur in PARK2-related PD. This information may inform future studies aiming to unveil primary signaling processes involved in PD and related neurodegenerative disorders.

scholarly journals A Lewy-testes demencia klinikai és neuropatológiai jellemzői

2017 ◽  
Vol 158 (17) ◽  
pp. 643-652 ◽  
Author(s):  
János Bencze ◽  
Viktória Simon ◽  
Erika Bereczki ◽  
Réka Majer ◽  
Gréta Varkoly ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Imaging Techniques ◽  
Lewy Bodies ◽  
Ubiquitin Proteasome System ◽  
Accurate Diagnosis ◽  
Lewy Neurites ◽  
Atypical Clinical Presentation ◽  
Neurodegenerative Dementia ◽  
Ubiquitin Proteasome

Abstract: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia. The accurate diagnosis is often possible only by neuropathological examination. The morphologic hallmarks are the presence of α-synuclein-rich Lewy bodies and Lewy neurites, identical to those seen in Parkinson’s disease (PD) and Parkinson’s disease dementia (PDD). Neurotransmitter deficits, synaptic and ubiquitin-proteasome system (UPS) dysfunction play major role in the pathomechanism. Characteristic symptoms are cognitive fluctuation, parkinsonism and visual hallucinations. Due to the often atypical clinical presentation novel imaging techniques and biomarkers could help the early diagnosis. Although curative treatment is not available, therapies can improve quality of life. Clinicopathological studies are important in exploring pathomechanisms, ensuring accurate diagnosis and identifying therapeutic targets. Orv Hetil. 2017; 158(17): 643–652.

scholarly journals Mechanistic Insights Expatiating the Redox-Active-Metal-Mediated Neuronal Degeneration in Parkinson’s Disease

2022 ◽  
Vol 23 (2) ◽  
pp. 678
Author(s):  
Tapan Behl ◽  
Piyush Madaan ◽  
Aayush Sehgal ◽  
Sukhbir Singh ◽  
Md Khalid Anwer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Degeneration ◽  
Lewy Bodies ◽  
Ubiquitin Proteasome System ◽  
Substantia Nigra Pars Compacta ◽  
Ros Generation ◽  
Redox Active ◽  
Ubiquitin Proteasome ◽  
The Central Nervous System

Parkinson’s disease (PD) is a complicated and incapacitating neurodegenerative malady that emanates following the dopaminergic (DArgic) nerve cell deprivation in the substantia nigra pars compacta (SN-PC). The etiopathogenesis of PD is still abstruse. Howbeit, PD is hypothesized to be precipitated by an amalgamation of genetic mutations and exposure to environmental toxins. The aggregation of α-synucelin within the Lewy bodies (LBs), escalated oxidative stress (OS), autophagy-lysosome system impairment, ubiquitin-proteasome system (UPS) impairment, mitochondrial abnormality, programmed cell death, and neuroinflammation are regarded as imperative events that actively participate in PD pathogenesis. The central nervous system (CNS) relies heavily on redox-active metals, particularly iron (Fe) and copper (Cu), in order to modulate pivotal operations, for instance, myelin generation, synthesis of neurotransmitters, synaptic signaling, and conveyance of oxygen (O2). The duo, namely, Fe and Cu, following their inordinate exposure, are viable of permeating across the blood–brain barrier (BBB) and moving inside the brain, thereby culminating in the escalated OS (through a reactive oxygen species (ROS)-reliant pathway), α-synuclein aggregation within the LBs, and lipid peroxidation, which consequently results in the destruction of DArgic nerve cells and facilitates PD emanation. This review delineates the metabolism of Fe and Cu in the CNS, their role and disrupted balance in PD. An in-depth investigation was carried out by utilizing the existing publications obtained from prestigious medical databases employing particular keywords mentioned in the current paper. Moreover, we also focus on decoding the role of metal complexes and chelators in PD treatment. Conclusively, metal chelators hold the aptitude to elicit the scavenging of mobile/fluctuating metal ions, which in turn culminates in the suppression of ROS generation, and thereby prelude the evolution of PD.

scholarly journals Phosphorylatedα-Synuclein-Copper Complex Formation in the Pathogenesis of Parkinson’s Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Juan Antonio Castillo-Gonzalez ◽  
Maria De Jesus Loera-Arias ◽  
Odila Saucedo-Cardenas ◽  
Roberto Montes-de-Oca-Luna ◽  
Aracely Garcia-Garcia ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Complex Formation ◽  
Protein Aggregation ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Ubiquitin Proteasome System ◽  
Aggregation Process ◽  
Neurodegenerative Process ◽  
Ubiquitin Proteasome

Parkinson’s disease is the second most important neurodegenerative disorder worldwide. It is characterized by the presence of Lewy bodies, which are mainly composed ofα-synuclein and ubiquitin-bound proteins. Both the ubiquitin proteasome system (UPS) and autophagy-lysosomal pathway (ALS) are altered in Parkinson’s disease, leading to aggregation of proteins, particularlyα-synuclein. Interestingly, it has been observed that copper promotes the protein aggregation process. Additionally, phosphorylation ofα-synuclein along with copper also affects the protein aggregation process. The interrelation amongα-synuclein phosphorylation and its capability to interact with copper, with the subsequent disruption of the protein degradation systems in the neurodegenerative process of Parkinson’s disease, will be analyzed in detail in this review.

scholarly journals Progress in the pathogenesis and genetics of Parkinson's disease

2008 ◽  
Vol 363 (1500) ◽  
pp. 2215-2227 ◽  
Author(s):  
Yoshikuni Mizuno ◽  
Nobutaka Hattori ◽  
Shin-ichiro Kubo ◽  
Shigeto Sato ◽  
Kenya Nishioka ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Disease Process ◽  
Ubiquitin Proteasome System ◽  
Neurodegenerative Process ◽  
Molecular Events ◽  
Ubiquitin Proteasome ◽  
Sporadic Parkinson’S Disease ◽  
Synuclein Proteins

Recent progresses in the pathogenesis of sporadic Parkinson's disease (PD) and genetics of familial PD are reviewed. There are common molecular events between sporadic and familial PD, particularly between sporadic PD and PARK1 -linked PD due to α - synuclein ( SNCA ) mutations. In sporadic form, interaction of genetic predisposition and environmental factors is probably a primary event inducing mitochondrial dysfunction and oxidative damage resulting in oligomer and aggregate formations of α-synuclein. In PARK1 -linked PD, mutant α-synuclein proteins initiate the disease process as they have increased tendency for self-aggregation. As highly phosphorylated aggregated proteins are deposited in nigral neurons in PD, dysfunctions of proteolytic systems, i.e. the ubiquitin–proteasome system and autophagy–lysosomal pathway, seem to be contributing to the final neurodegenerative process. Studies on the molecular mechanisms of nigral neuronal death in familial forms of PD will contribute further on the understanding of the pathogenesis of sporadic PD.

Ubiquitin–proteasome system and Parkinson's disease

2006 ◽  
Vol 21 (11) ◽  
pp. 1806-1823 ◽  
Author(s):  
C. Warren Olanow ◽  
Kevin St. P. McNaught
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

scholarly journals α-synuclein pathogenesis in hiPSC models of Parkinson’s Disease

2021 ◽  
Author(s):  
Leo R Quinlan ◽  
Jara Maria Baena-Montes ◽  
Sahar Avazzadeh
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Modeling ◽  
Viral Vector ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Model Systems ◽  
The Brain

α-synuclein is an increasingly prominent player in the pathology of a variety of neurodegenerative conditions. Parkinson’s disease (PD) is a neurodegenerative disorder that affects mainly the dopaminergic neurons in the substantia nigra of the brain. Typical of PD pathology is the finding of protein aggregations termed ‘Lewy bodies’ in the brain regions affected. α-synuclein is implicated in many disease states including dementia with Lewy bodies and Alzheimer’s disease. However, PD is the most common synucleinopathy and continues to be a significant focus of PD research in terms of the α-synuclein Lewy body pathology. Mutations in several genes are associated with PD development including SNCA, which encodes α-synuclein. A variety of model systems have been employed to study α-synuclein physiology and pathophysiology in an attempt to relate more closely to PD pathology. These models include cellular and animal system exploring transgenic technologies, viral vector expression and knockdown approaches, and models to study the potential prion protein-like effects of α-synuclein. The current review focuses on human induced pluripotent stem cell (iPSC) models with a specific focus on mutations or multiplications of the SNCA gene. iPSCs are a rapidly evolving technology with huge promise in the study of normal physiology and disease modeling in vitro. The ability to maintain a patient's genetic background and replicate similar cell phenotypes make iPSCs a powerful tool in the study of neurological diseases. This review focus on the current knowledge about α-synuclein physiological function as well as its role in PD pathogenesis based on human iPSC models.

scholarly journals Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia

2020 ◽  
Vol 21 (11) ◽  
pp. 3779 ◽  
Author(s):  
Ichiro Kawahata ◽  
Kohji Fukunaga
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Tyrosine Hydroxylase ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
The Novel ◽  
Gene Encoding ◽  
Dopaminergic Systems ◽  
Dopamine Biosynthesis ◽  
Ubiquitin Proteasome

Nigrostriatal dopaminergic systems govern physiological functions related to locomotion, and their dysfunction leads to movement disorders, such as Parkinson’s disease and dopa-responsive dystonia (Segawa disease). Previous studies revealed that expression of the gene encoding nigrostriatal tyrosine hydroxylase (TH), a rate-limiting enzyme of dopamine biosynthesis, is reduced in Parkinson’s disease and dopa-responsive dystonia; however, the mechanism of TH depletion in these disorders remains unclear. In this article, we review the molecular mechanism underlying the neurodegeneration process in dopamine-containing neurons and focus on the novel degradation pathway of TH through the ubiquitin-proteasome system to advance our understanding of the etiology of Parkinson’s disease and dopa-responsive dystonia. We also introduce the relation of α-synuclein propagation with the loss of TH protein in Parkinson’s disease as well as anticipate therapeutic targets and early diagnosis of these diseases.

Reciprocal Upshot of Nitric Oxide, Endoplasmic Reticulum Stress, and Ubiquitin Proteasome System in Parkinson’s Disease Pathology

2020 ◽  
pp. 107385842094221
Author(s):  
Shubhangini Tiwari ◽  
Sarika Singh
Keyword(s):  
Nitric Oxide ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Neuronal Degeneration ◽  
Early Stage ◽  
Ubiquitin Proteasome System ◽  
Disease Etiology ◽  
Ubiquitin Proteasome

Parkinson’s disease (PD) pathology involves degeneration of nigrostriatal pathway, postulating symptoms associated with age, environment, and genetic anomalies, including nonlinear disease progression. Hallmark characteristics of PD include dopaminergic neuronal degeneration and death, which may also be exhibited by other neurological diseases, making the diagnosis of the disease intricate at early stage. Such obscure diagnosis of the disease, limited symptomatic improvements with available therapeutics, and their inability to modify the disease status instigate us to appraise the past research and formulate the colligating comprehensive insights. This review is accentuating on the role of nitric oxide, endoplasmic reticulum stress, and their association with the ubiquitin proteasome system (UPS) during PD pathology involving focus on ubiquitin ligases due to their regulatory functions. Meticulous understanding of these major disease-related pathological events and their functional alliance may render novel dimensions for better understanding of disease etiology, related mechanisms, as well as direction toward witnessing of new therapeutic targets for the management of Parkinson’s patients.

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