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 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 Mitochondrial Dysfunction, Protein Misfolding and Neuroinflammation in Parkinson’s Disease: Roads to Biomarker Discovery

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1508
Author(s):  
Anna Picca ◽  
Flora Guerra ◽  
Riccardo Calvani ◽  
Roberta Romano ◽  
Hélio José Coelho-Júnior ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Protein Misfolding ◽  
Biomarker Discovery ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Lewy Neurites ◽  
Post Translational Modifications ◽  
Ubiquitin Proteasome

Parkinson’s Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery.

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 Fibroblast Growth Factor 20 Gene Polymorphism in Parkinson’s Disease in Asian Population: A Meta-Analysis

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 674
Author(s):  
Han-Lin Chiang ◽  
Yih-Ru Wu ◽  
Yi-Chun Chen ◽  
Hon-Chung Fung ◽  
Chiung-Mei Chen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Meta Analysis ◽  
Lewy Bodies ◽  
Asian Population ◽  
Protective Role ◽  
Lewy Neurites ◽  
Chinese Populations ◽  
Study Results

Parkinson’s disease (PD) is a neurodegenerative disease with the pathological hallmark of Lewy bodies and Lewy neurites composed of α-synuclein. The SNP rs591323 is one of the risk loci located near the FGF20 gene that has been implicated in PD. The variation of FGF20 in the 3′ untranslated region was shown to increase α-synuclein expression. We examined the association of rs591323 with the risk of PD in a Taiwanese population and conducted a meta-analysis, including our study and two other studies from China, to further confirm the role of this SNP in Taiwanese/Chinese populations. A total of 586 patients with PD and 586 health controls (HCs) were included in our study. We found that the minor allele (A) and the AA + GA genotype under the dominant model are significantly less frequent in PD than in controls. The meta-analysis consisted of 1950 patients with PD and 2073 healthy controls from three studies. There was significant association between rs591323 and the risk of PD in the additive (Z = −3.96; p < 0.0001) and the dominant models (Z = −4.01; p < 0.0001). Our study results and the meta-analysis support the possible protective role of the rs591323 A allele in PD in Taiwanese/Chinese populations.

scholarly journals Cryo-EM structure of alpha-synuclein fibrils

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ricardo Guerrero-Ferreira ◽  
Nicholas MI Taylor ◽  
Daniel Mona ◽  
Philippe Ringler ◽  
Matthias E Lauer ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Diagnosis And Treatment ◽  
Lewy Neurites ◽  
Cryo Electron Microscopy ◽  
High Concentrations ◽  
Hydrophobic Cleft

Parkinson’s disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1–121), determined by cryo-electron microscopy at a resolution of 3.4 Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50–57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.

scholarly journals Parkinson’s disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM

2020 ◽  
Vol 117 (33) ◽  
pp. 20305-20315 ◽  
Author(s):  
Kun Zhao ◽  
Yeh-Jun Lim ◽  
Zhenying Liu ◽  
Houfang Long ◽  
Yunpeng Sun ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Posttranslational Modifications ◽  
Cortical Neurons ◽  
Amyloid Fibrils ◽  
Lewy Bodies ◽  
Interaction Network ◽  
Lewy Neurites ◽  
Cryo Electron Microscopy ◽  
Fibril Structure

Posttranslational modifications (PTMs) of α-synuclein (α-syn), e.g., phosphorylation, play an important role in modulating α-syn pathology in Parkinson’s disease (PD) and α-synucleinopathies. Accumulation of phosphorylated α-syn fibrils in Lewy bodies and Lewy neurites is the histological hallmark of these diseases. However, it is unclear how phosphorylation relates to α-syn pathology. Here, by combining chemical synthesis and bacterial expression, we obtained homogeneous α-syn fibrils with site-specific phosphorylation at Y39, which exhibits enhanced neuronal pathology in rat primary cortical neurons. We determined the cryo-electron microscopy (cryo-EM) structure of the pY39 α-syn fibril, which reveals a fold of α-syn with pY39 in the center of the fibril core forming an electrostatic interaction network with eight charged residues in the N-terminal region of α-syn. This structure composed of residues 1 to 100 represents the largest α-syn fibril core determined so far. This work provides structural understanding on the pathology of the pY39 α-syn fibril and highlights the importance of PTMs in defining the polymorphism and pathology of amyloid fibrils in neurodegenerative diseases.

Dementia with Lewy bodies and Parkinson’s disease dementia

2013 ◽  
Author(s):  
Arvid Rongve ◽  
Dag Aarsland
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dementia With Lewy Bodies ◽  
Clinical Symptoms ◽  
Imaging Techniques ◽  
Lewy Bodies ◽  
Epidemiological Data ◽  
Parkinson’S Disease Dementia ◽  
Esterase Inhibitors ◽  
Staging Systems

Dementia with Lewy bodies and Parkinson’s disease dementia belong to the α-synucleinopathies, a family of diseases pathologically characterized by aggregation of α-synuclein in Lewy bodies in the brain. In this chapter we present the epidemiological data for both conditions including new data on MCI. Clinical diagnostic criteria are reviewed and the different neuropathology staging systems for DLB and PDD and the most important genetic findings are considered. Biomarkers in DLB and PDD with particular focus on imaging techniques like CIT-SPECT and MRI are described. Important clinical symptoms in both conditions are presented in detail and the most important clinical differential diagnoses are discussed. Pharmacological and non- pharmacological treatment of different symptoms in both conditions are discussed with particular emphasis on the choline esterase inhibitors and antipsychotic medications.New data on memantine are presented.

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
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