scholarly journals Mitochondrial Dysfunction andα-Synuclein Synaptic Pathology in Parkinson’s Disease: Who’s on First?

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Michela Zaltieri ◽  
Francesca Longhena ◽  
Marina Pizzi ◽  
Cristina Missale ◽  
PierFranco Spano ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Nigrostriatal System ◽  
Primary Role ◽  
Lewy Neurites ◽  
Synaptic Pathology ◽  
Lines Of Evidence

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Its characteristic neuropathological features encompass the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies and Lewy neurites. These are intraneuronal and intraneuritic proteinaceous insoluble aggregates whose main constituent is the synaptic proteinα-synuclein. Compelling lines of evidence indicate that mitochondrial dysfunction andα-synuclein synaptic deposition may play a primary role in the onset of this disorder. However, it is not yet clear which of these events may come first in the sequel of processes leading to neurodegeneration. Here, we reviewed data supporting either thatα-synuclein synaptic deposition precedes and indirectly triggers mitochondrial damage or that mitochondrial deficits lead to neuronal dysfunction andα-synuclein synaptic accumulation. The present overview shows that it is still difficult to establish the exact temporal sequence and contribution of these events to PD.

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 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.

α-Synuclein in Parkinson’s Disease: Does a Prion-Like Mechanism of Propagation from Periphery to the Brain Play a Role?

2020 ◽  
pp. 107385842094318
Author(s):  
Huimin Zheng ◽  
Changhe Shi ◽  
Haiyang Luo ◽  
Liyuan Fan ◽  
Zhihua Yang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Cellular Level ◽  
Motor Symptoms ◽  
Lewy Neurites ◽  
Growing Body ◽  
Non Motor Symptoms ◽  
The Brain

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, defined as motor and non-motor symptoms associated with the loss of dopaminergic neurons and a decreased release of dopamine (DA). Currently, PD patients are believed to have a neuropathological basis denoted by the presence of Lewy bodies (LBs) or Lewy neurites (LNs), which mostly comprise α-synuclein (α-syn) inclusions. Remarkably, there is a growing body of evidence indicating that the inclusions undergo template-directed aggregation and propagation via template-directed among the brain and peripheral organs, mainly in a prion-like manner. Interestingly, some studies reported that an integral loop was reminiscent of the mechanism of Parkinson’s disease, denoting that α-syn as prionoid was transmitted from the periphery to the brain via specific pathways. Also the systematic life cycle of α-syn in the cellular level is illustrated. In this review, we critically assess landmark evidence in the field of Parkinson’s disease with a focus on the genesis and prion-like propagation of the α-syn pathology. The anatomical and cell-to-cell evidences are discussed to depict the theory behind the propagation and transferred pathways. Furthermore, we highlight effective therapeutic perspectives and clinical trials targeting prion-like mechanisms. Major controversies surrounding this topic are also discussed.

scholarly journals Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

2018 ◽  
Vol 115 (41) ◽  
pp. 10481-10486 ◽  
Author(s):  
Jordi Pujols ◽  
Samuel Peña-Díaz ◽  
Diana F. Lázaro ◽  
Francesca Peccati ◽  
Francisca Pinheiro ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Small Molecule ◽  
Dopaminergic Neurons ◽  
High Throughput Screening ◽  
Protein Misfolding ◽  
Lewy Bodies ◽  
Molar Ratio ◽  
Lewy Neurites

Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of α-synuclein. Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein. SynuClean-D–treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein–induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson’s disease.

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 Imaging mass cytometry reveals generalised deficiency in OXPHOS complexes in Parkinson’s disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Chun Chen ◽  
David McDonald ◽  
Alasdair Blain ◽  
Ashwin Sachdeva ◽  
Laura Bone ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Dopaminergic Neurons ◽  
Neuronal Response ◽  
Proteomic Profiling ◽  
Mass Cytometry ◽  
And Control

AbstractHere we report the application of a mass spectrometry-based technology, imaging mass cytometry, to perform in-depth proteomic profiling of mitochondrial complexes in single neurons, using metal-conjugated antibodies to label post-mortem human midbrain sections. Mitochondrial dysfunction, particularly deficiency in complex I has previously been associated with the degeneration of dopaminergic neurons in Parkinson’s disease. To further our understanding of the nature of this dysfunction, and to identify Parkinson’s disease specific changes, we validated a panel of antibodies targeting subunits of all five mitochondrial oxidative phosphorylation complexes in dopaminergic neurons from Parkinson’s disease, mitochondrial disease, and control cases. Detailed analysis of the expression profile of these proteins, highlighted heterogeneity between individuals. There is a widespread decrease in expression of all complexes in Parkinson’s neurons, although more severe in mitochondrial disease neurons, however, the combination of affected complexes varies between the two groups. We also provide evidence of a potential neuronal response to mitochondrial dysfunction through a compensatory increase in mitochondrial mass. This study highlights the use of imaging mass cytometry in the assessment and analysis of expression of oxidative phosphorylation proteins, revealing the complexity of deficiencies of these proteins within individual neurons which may contribute to and drive neurodegeneration in Parkinson’s disease.

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 Elevated COUP-TFII expression in dopaminergic neurons accelerates the progression of Parkinson’s disease through mitochondrial dysfunction

PLoS Genetics ◽  
2020 ◽  
Vol 16 (6) ◽  
pp. e1008868
Author(s):  
Chung-Yang Kao ◽  
Mafei Xu ◽  
Leiming Wang ◽  
Shih-Chieh Lin ◽  
Hui-Ju Lee ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Dopaminergic Neurons

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.

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.

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