scholarly journals Interaction between coxsackievirus B3 infection and α-synuclein in models of Parkinson’s disease

2021 ◽  
Vol 17 (10) ◽  
pp. e1010018
Author(s):  
Soo Jin Park ◽  
Uram Jin ◽  
Sang Myun Park
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inclusion Body ◽  
Dopaminergic Neurons ◽  
Inclusion Bodies ◽  
Lewy Bodies ◽  
Coxsackievirus B3 ◽  
Body Formation ◽  
Inclusion Body Formation ◽  
Cvb3 Infection

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. PD is pathologically characterized by the death of midbrain dopaminergic neurons and the accumulation of intracellular protein inclusions called Lewy bodies or Lewy neurites. The major component of Lewy bodies is α-synuclein (α-syn). Prion-like propagation of α-syn has emerged as a novel mechanism in the progression of PD. This mechanism has been investigated to reveal factors that initiate Lewy pathology with the aim of preventing further progression of PD. Here, we demonstrate that coxsackievirus B3 (CVB3) infection can induce α-syn-associated inclusion body formation in neurons which might act as a trigger for PD. The inclusion bodies contained clustered organelles, including damaged mitochondria with α-syn fibrils. α-Syn overexpression accelerated inclusion body formation and induced more concentric inclusion bodies. In CVB3-infected mice brains, α-syn aggregates were observed in the cell body of midbrain neurons. Additionally, α-syn overexpression favored CVB3 replication and related cytotoxicity. α-Syn transgenic mice had a low survival rate, enhanced CVB3 replication, and exhibited neuronal cell death, including that of dopaminergic neurons in the substantia nigra. These results may be attributed to distinct autophagy-related pathways engaged by CVB3 and α-syn. This study elucidated the mechanism of Lewy body formation and the pathogenesis of PD associated with CVB3 infection.

scholarly journals Interaction Between Coxsackievirus B3 Infection and α-Synuclein in Parkinson’s Disease

2021 ◽  
Author(s):  
Soo Jin Park ◽  
Uram Jin ◽  
Sang Myun Park
Keyword(s):  
Parkinson’S Disease ◽  
Inclusion Body ◽  
Dopaminergic Neurons ◽  
Lewy Body ◽  
Inclusion Bodies ◽  
Lewy Bodies ◽  
Coxsackievirus B3 ◽  
Body Formation ◽  
Inclusion Body Formation ◽  
Cvb3 Infection

Abstract BackgroundParkinson's disease (PD) is one of the most common neurodegenerative disease. PD is pathologically characterized by the death of midbrain dopaminergic neurons and the accumulation of intracellular protein inclusions called Lewy bodies or Lewy neurites. The major component of Lewy bodies is α-synuclein (α-syn). Prion-like propagation of α-syn has emerged as a novel mechanism in the progression of PD. Targeting this mechanism could enable the development of disease-modifying therapies for patients with PD. Nevertheless, the initial triggers of LB formation leading to acceleration of the process remain elusive.MethodsTo evaluate α-syn function in viral replication, we infected coxsackievirus B3 (CVB3) to α-syn overexpressed neurons or α-syn transgenic (TG) mice. We then performed biochemical and histological analyses to evaluate interaction between CVB3 and α-syn in Lewy body formation.ResultsWe demonstrated that CVB3 infection can induce α-syn-associated inclusion body formation in neurons as a trigger. The inclusion bodies contained clustered organelles, including damaged mitochondria with α-syn fibrils. α-Syn overexpression accelerated inclusion body formation and induced more concentric inclusion bodies. In brains from CVB3 infected mice, α-syn aggregates in the cell body of midbrain neurons were observed. Additionally, α-syn overexpression favored CVB3 replication and related cytotoxicity. α-Syn transgenic mice had a low survival rate, enhanced CVB3 replication, and further neuronal cell death, including dopaminergic neurons in the substantia nigra. These results may be due to the different usage of autophagy between CVB3 and α-syn. ConclusionsThis study elucidated the mechanism of Lewy body formation and the pathogenesis of PD associated with CVB3 infection.

Absence of inclusion body formation in the MPTP mouse model of Parkinson's disease

2005 ◽  
Vol 134 (1) ◽  
pp. 103-108 ◽  
Author(s):  
Mika Shimoji ◽  
Li Zhang ◽  
Allen S. Mandir ◽  
Valina L. Dawson ◽  
Ted M. Dawson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Inclusion Body ◽  
Body Formation ◽  
Inclusion Body Formation

scholarly journals Dysfunction of mitochondria as the basis of Parkinson’s disease

2018 ◽  
Vol 6 (4) ◽  
pp. 174-181
Author(s):  
Małgorzata Popis
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Dopaminergic Neurons ◽  
Genetic Factors ◽  
Lewy Bodies ◽  
Main Ingredient ◽  
Mitochondrial Dynamic ◽  
Factors Affecting

AbstractParkinson's disease is the second most common neurodegenerative disease, affecting about 0,15-0,3% of the world's population. Its characteristic feature is a loss of dopaminergic neurons in the substantia nigra. PD leads to dopamine deficiency and formation of intracellular inclusions called Lewy bodies, whose main ingredient is α-synuclein. Other types of nervous system cells are also affected by changes associated with that disease. The underlying molecular pathogenesis involves multiple pathways and mechanisms: mitochondrial function, oxidative stress, genetic factors, α-synuclein proteostasis, mitochondrial dynamic impairment, and disorders of the mitophagy process. This review summarizes the factors affecting the functioning of the mitochondria and their connection to the development of Parkinson's disease.

scholarly journals Ubiquitin versus misfolding: The minimal requirements for inclusion body formation

2016 ◽  
Vol 213 (2) ◽  
pp. 147-149 ◽  
Author(s):  
Nico P. Dantuma ◽  
Florian A. Salomons
Keyword(s):  
Neurodegenerative Diseases ◽  
Inclusion Body ◽  
Protein Misfolding ◽  
Inclusion Bodies ◽  
Functional Role ◽  
Body Formation ◽  
Protein Deposits ◽  
Cell Biol ◽  
Inclusion Body Formation ◽  
Characteristic Features

Ubiquitin-containing inclusion bodies are characteristic features of numerous neurodegenerative diseases, but whether ubiquitin plays a functional role in the formation of these protein deposits is unclear. In this issue, Bersuker et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201511024) report that protein misfolding without ubiquitylation is sufficient for translocation into inclusion bodies.

scholarly journals Ebola virus inclusion body formation and RNA synthesis are controlled by a novel domain of NP interacting with VP35

2020 ◽  
Author(s):  
Tsuyoshi Miyake ◽  
Charlotte M. Farley ◽  
Benjamin E. Neubauer ◽  
Thomas P. Beddow ◽  
Thomas Hoenen ◽  
...  
Keyword(s):  
Life Cycle ◽  
Inclusion Body ◽  
Inclusion Bodies ◽  
Rna Synthesis ◽  
Ebola Virus ◽  
Rna Replication ◽  
Viral Rna ◽  
Central Domain ◽  
Body Formation ◽  
Inclusion Body Formation

AbstractEbola virus (EBOV) inclusion bodies (IBs) are cytoplasmic sites of nucleocapsid formation and RNA replication, housing key steps in the virus life cycle that warrant further investigation. During infection IBs display dynamic properties regarding their size and location. Also, the contents of IBs must transition prior to further viral maturation, assembly and release, implying additional steps in IB function. Interestingly, expression of the viral nucleoprotein (NP) alone is sufficient for generation of IBs, indicating that it plays an important role in IB formation during infection. In addition to NP, other components of the nucleocapsid localize to IBs, including VP35, VP24, VP30 and the RNA polymerase L. Previously we defined and solved the crystal structure of the C-terminal domain of NP (NP-Ct), but its role in virus replication remained unclear. Here we show that NP-Ct is absolutely required for IB formation when NP is expressed alone. Interestingly, we find that NP-Ct is also required for production of infectious virus-like particles and retention of viral RNA within these particles. Furthermore, co-expression of the nucleocapsid component VP35 overcomes deletion of NP-Ct in triggering IB formation, demonstrating a functional interaction between the two proteins. Of all the EBOV proteins only VP35 is able to overcome the defect in IB formation caused by deletion of NP-Ct. This effect is mediated by a novel protein-protein interaction between VP35 and NP that controls both regulation of IB formation and RNA replication itself, and which is mediated by a newly identified domain of NP, the “central domain” (CD).ImportanceInclusion bodies (IBs) are cytoplasmic sites of RNA synthesis for a variety of negative sense RNA viruses including Ebola virus. In addition to housing important steps in the viral life cycle, IBs protect new viral RNA from innate immune attack and contain specific host proteins whose function is under study. A key viral factor in Ebola virus IB formation is the nucleoprotein, NP, which also is important in RNA encapsidation and synthesis. In this study, we have identified two domains of NP that control inclusion body formation. One of these, the central domain (CD), interacts with viral protein VP35 to control both inclusion body formation and RNA synthesis. The other is the NP C-terminal domain (NP-Ct), whose function has not previously been reported. These findings contribute to a model in which NP and its interactions with VP35 link the establishment of IBs to the synthesis of viral RNA.

scholarly journals Presence of genetic polymorphisms may impact on predisposition to Parkinson’s disease

2021 ◽  
Author(s):  
Rubens Barbosa Rezende ◽  
Larissa Teodoro
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
High Risk ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Single Nucleotide ◽  
Asian Populations ◽  
Lrrk2 Gene ◽  
The Impact ◽  
Reduced Risk

Introduction: Parkinson’s disease (PD) is characterized by the degeneration and loss of dopaminergic neurons in the black substantia and the formation of Lewy bodies, thus being considered a neurodegenerative disease. Thus, the objective was to understand the impact of polymorphisms in the predisposition to PD. Methods: It’s a narrative review of literature in the PubMed and SciELO databases, using the descriptors: “Polymorphism, Single Nucleotide” and “Parkinson disease”, registered in DeCS/MeSH, and using the Boolean operator AND. The inclusion criteria were: complete articles and made available free of charge, published in English, Spanish and Portuguese, between 2016 and January 2021. Results: After the research, 167 publications were found and seven were included. The data from the first study indicate that the rs33949390 of the LRRK2 gene helps in predisposition to PD in Asian populations, mainly Chinese. The second study indicated that the NFE2L2 rs6721961 allele was linked to a reduced risk of PD. The third study found that the GSK3B rs1732170, STK11 rs8111699, SNCA rs356219 and FCHSD1 rs456998 polymorphisms were linked to a high risk of PD. The fourth study found that the SNCA variants rs7684318, rs356220, rs356203 and rs2736990 were linked to the disease and were at high risk of developing PD in the Mexican population. The fifth and sixth study are meta-analyzes, the fifth confirming the lower allele rs11558538 of HNMT is associated with a reduced risk of developing PD. And the sixth assumes a possible link between CCDC62 rs12817488 and the risk of PD in the Chinese population. Conclusion: However, the analyzed data indicate that the polymorphisms contributed to the susceptibility to PD, however further studies related to the polymorphisms and their relationship to PD are still needed for more ethnic groups, and thus early diagnosis is possible.

scholarly journals Two Types of Spheroid Bodies in the Nigral Neurons in Parkinson's Disease

1991 ◽  
Vol 18 (3) ◽  
pp. 287-294 ◽  
Author(s):  
Tatsuo Yamada ◽  
Haruhiko Akiyama ◽  
Patrick L. McGeer
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Staining Pattern ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Striatonigral Degeneration ◽  
Neurologically Normal ◽  
Normal Controls ◽  
Dystrophic Dendrites

ABSTRACT:Dendritic spheroid bodies (SBs) and Lewy bodies (LBs) were identified in comparable numbers in the substantia nigra pars compacta (SBC) of nine parkinsonian cases and one case of striatonigral degeneration but were not found irt cases of Huntington's disease or neurologically normal controls. The immunohistochemical profile of the SBs in dystrophic dendrites of nigrostriatal dopaminergic neurons was remarkably similar to that of the LBs found within dendrites or free of the SNC neuropil. Both types of inclusions stained positively with antibodies to tyrosine hydroxylase, ubiquitin and microtubule-associated protein-2 (MAP2), and negatively for Tau-2, although they had different ultrastructural appearances. A few intracellular LBs were stained by antibodies to neurofilament proteins (NFs) 68, 160, and 200 kD, but dendritic SBs and extracellular LBs were not so stained. These data indicate that dendritic SBs and extracellular LBs may have a common molecular pathogenetic origin in Parkinson's disease. On the other hand, the SBs seen in the pars reticulata (SNR) and in the distal nigrostriatal axons even in control cases were generally stained by antibodies to NFs and ubiquitin but not to MAP2. This latter staining pattern in similar to that shown by SBs in the anterior horn in ALS and in the cerebellum of neurologically normal brains and is believed typical of axonal as opposed to dendritic SBs.

scholarly journals Human Metapneumovirus Induces Formation of Inclusion Bodies for Efficient Genome Replication and Transcription

2017 ◽  
Vol 91 (24) ◽  
Author(s):  
Nicolás Cifuentes-Muñoz ◽  
Jean Branttie ◽  
Kerri Beth Slaughter ◽  
Rebecca Ellis Dutch
Keyword(s):  
Inclusion Body ◽  
Inclusion Bodies ◽  
Time Course ◽  
Human Metapneumovirus ◽  
Genome Replication ◽  
Body Formation ◽  
Inclusion Body Formation ◽  
Genome Transcription ◽  
Infected Cells ◽  
Transcription And Replication

ABSTRACT Human metapneumovirus (HMPV) causes significant upper and lower respiratory disease in all age groups worldwide. The virus possesses a negative-sense single-stranded RNA genome of approximately 13.3 kb encapsidated by multiple copies of the nucleoprotein (N), giving rise to helical nucleocapsids. In addition, copies of the phosphoprotein (P) and the large RNA polymerase (L) decorate the viral nucleocapsids. After viral attachment, endocytosis, and fusion mediated by the viral glycoproteins, HMPV nucleocapsids are released into the cell cytoplasm. To visualize the subsequent steps of genome transcription and replication, a fluorescence in situ hybridization (FISH) protocol was established to detect different viral RNA subpopulations in infected cells. The FISH probes were specific for detection of HMPV positive-sense RNA (+RNA) and viral genomic RNA (vRNA). Time course analysis of human bronchial epithelial BEAS-2B cells infected with HMPV revealed the formation of inclusion bodies (IBs) from early times postinfection. HMPV IBs were shown to be cytoplasmic sites of active transcription and replication, with the translation of viral proteins being closely associated. Inclusion body formation was consistent with an actin-dependent coalescence of multiple early replicative sites. Time course quantitative reverse transcription-PCR analysis suggested that the coalescence of inclusion bodies is a strategy to efficiently replicate and transcribe the viral genome. These results provide a better understanding of the steps following HMPV entry and have important clinical implications. IMPORTANCE Human metapneumovirus (HMPV) is a recently discovered pathogen that affects human populations of all ages worldwide. Reinfections are common throughout life, but no vaccines or antiviral treatments are currently available. In this work, a spatiotemporal analysis of HMPV replication and transcription in bronchial epithelial cell-derived immortal cells was performed. HMPV was shown to induce the formation of large cytoplasmic granules, named inclusion bodies, for genome replication and transcription. Unlike other cytoplasmic structures, such as stress granules and processing bodies, inclusion bodies are exclusively present in infected cells and contain HMPV RNA and proteins to more efficiently transcribe and replicate the viral genome. Though inclusion body formation is nuanced, it corresponds to a more generalized strategy used by different viruses, including filoviruses and rhabdoviruses, for genome transcription and replication. Thus, an understanding of inclusion body formation is crucial for the discovery of innovative therapeutic targets.

scholarly journals Toxin-Induced and Genetic Animal Models of Parkinson's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Shin Hisahara ◽  
Shun Shimohama
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Mitochondrial Dysfunction ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Causative Factors ◽  
Genetically Determined

Parkinson's disease (PD) is a common progressive neurodegenerative disorder. The major pathological hallmarks of PD are the selective loss of nigrostriatal dopaminergic neurons and the presence of intraneuronal aggregates termed Lewy bodies (LBs), but the pathophysiological mechanisms are not fully understood. Epidemiologically, environmental neurotoxins such as pesticides are promising candidates for causative factors of PD. Oxidative stress and mitochondrial dysfunction induced by these toxins could contribute to the progression of PD. While most cases of PD are sporadic, specific mutations in genes that cause familial forms of PD have led to provide new insights into its pathogenesis. This paper focuses on animal models of both toxin-induced and genetically determined PD that have provided significant insight for understanding this disease. We also discuss the validity, benefits, and limitations of representative models.

scholarly journals Alpha-Synuclein: The Interplay of Pathology, Neuroinflammation, and Environmental Factors in Parkinson’s Disease

2020 ◽  
Vol 20 (2-3) ◽  
pp. 55-64
Author(s):  
Songzhe He ◽  
Shan Zhong ◽  
Gang Liu ◽  
Jun Yang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Environmental Factors ◽  
Dopaminergic Neurons ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Future Directions ◽  
Main Protein ◽  
Cumulative Evidence

<b><i>Background:</i></b> Parkinson’s disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disease. α-Synuclein (α-syn), which is the main protein component of Lewy bodies, plays an important role in the pathological hallmarks of PD. However, the pathological function of α-syn and the molecular mechanisms responsible for the degeneration of dopaminergic neurons are still elusive. <b><i>Summary:</i></b> Cumulative evidence implicates that abnormal processing of α-syn will be predicted to lead to pathological changes in PD. <b><i>Key Messages:</i></b> In this review, we summarize the structure and physiological function of α-syn, and further discuss the interplay of pathology, neuroinflammation, and environmental factors in PD. Additionally, we suggest future directions for understanding the toxicity of α-syn to neurons, which may ultimately encourage us to better design disease-modifying therapeutic strategies for PD.

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