scholarly journals α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease

2012 ◽  
Vol 21 (14) ◽  
pp. 3173-3192 ◽  
Author(s):  
Isabel Lastres-Becker ◽  
Ayse Ulusoy ◽  
Nadia G. Innamorato ◽  
Gurdal Sahin ◽  
Alberto Rábano ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Aggregation ◽  
Neuronal Death ◽  
Early Stage

Association of the Non-Motor Burden with Patterns of Striatal Dopamine Loss in de novo Parkinson’s Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 1541-1549
Author(s):  
Seok Jong Chung ◽  
Sangwon Lee ◽  
Han Soo Yoo ◽  
Yang Hyun Lee ◽  
Hye Sun Lee ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
De Novo ◽  
Early Stage ◽  
Striatal Dopamine ◽  
Motor Deficits ◽  
Dopamine Depletion ◽  
Severe Motor ◽  
Severe Group ◽  
Striatal Dopamine Depletion

Background: Striatal dopamine deficits play a key role in the pathogenesis of Parkinson’s disease (PD), and several non-motor symptoms (NMSs) have a dopaminergic component. Objective: To investigate the association between early NMS burden and the patterns of striatal dopamine depletion in patients with de novo PD. Methods: We consecutively recruited 255 patients with drug-naïve early-stage PD who underwent 18F-FP-CIT PET scans. The NMS burden of each patient was assessed using the NMS Questionnaire (NMSQuest), and patients were divided into the mild NMS burden (PDNMS-mild) (NMSQuest score <6; n = 91) and severe NMS burden groups (PDNMS-severe) (NMSQuest score >9; n = 90). We compared the striatal dopamine transporter (DAT) activity between the groups. Results: Patients in the PDNMS-severe group had more severe parkinsonian motor signs than those in the PDNMS-mild group, despite comparable DAT activity in the posterior putamen. DAT activity was more severely depleted in the PDNMS-severe group in the caudate and anterior putamen compared to that in the PDMNS-mild group. The inter-sub-regional ratio of the associative/limbic striatum to the sensorimotor striatum was lower in the PDNMS-severe group, although this value itself lacked fair accuracy for distinguishing between the patients with different NMS burdens. Conclusion: This study demonstrated that PD patients with severe NMS burden exhibited severe motor deficits and relatively diffuse dopamine depletion throughout the striatum. These findings suggest that the level of NMS burden could be associated with distinct patterns of striatal dopamine depletion, which could possibly indicate the overall pathological burden in PD.

Gene expression analysis in modeling Parkinson’s disease

2020 ◽  
pp. 103-104
Author(s):  
М.М. Руденок ◽  
А.Х. Алиева ◽  
А.А. Колачева ◽  
М.В. Угрюмов ◽  
П.А. Сломинский ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Stage ◽  
Systemic Disease ◽  
Molecular Genetic ◽  
Presymptomatic Stage ◽  
Whole Transcriptome Analysis ◽  
Whole Transcriptome ◽  
The Brain ◽  
Transcriptome Level

Несмотря на очевидный прогресс, достигнутый в изучении молекулярно-генетических факторов и механизмов патогенеза болезни Паркинсона (БП), в настоящее время стало ясно, что нарушения в структуре ДНК не описывают весь спектр патологических изменений, наблюдаемых при развитии заболевания. В настоящее время показано, что существенное влияние на патогенез БП могут оказывать изменения на уровне транскриптома. В работе были использованы мышиные модели досимптомной стадии БП, поздней досимптомной и ранней симптомной (РСС) стадиями БП. Для полнотранскриптомного анализа пулов РНК тканей черной субстанции и стриатума мозга мышей использовались микрочипы MouseRef-8 v2.0 Expression BeadChip Kit («Illumina», США). Полученные данные указывают на последовательное вовлечение транскриптома в патогенез БП, а также на то, что изменения на транскриптомном уровне процессов транспорта и митохондриального биогенеза могут играть важную роль в нейродегенерации при БП уже на самых ранних этапах. Parkinson’s disease (PD) is a complex systemic disease, mainly associated with the death of dopaminergic neurons. Despite the obvious progress made in the study of molecular genetic factors and mechanisms of PD pathogenesis, it has now become clear that violations in the DNA structure do not describe the entire spectrum of pathological changes observed during the development of the disease. It has now been shown that changes at the transcriptome level can have a significant effect on the pathogenesis of PD. The authors used models of the presymptomatic stage of PD with mice decapitation after 6 hours (6 h-PSS), presymptomatic stage with decapitation after 24 hours (24 h-PSS), advanced presymptomatic (Adv-PSS) and early symptomatic (ESS) stages of PD. For whole transcriptome analysis of RNA pools of the substantia nigra and mouse striatum, the MouseRef-8 v2.0 Expression BeadChip Kit microchips (Illumina, USA) were used. As a result of the analysis of whole transcriptome data, it was shown that, there are a greater number of statistically significant changes in the tissues of the brain and peripheral blood of mice with Adv-PSS and ESS models of PD compared to 6 h-PSS and 24 h-PSS models. In general, the obtained data indicate the sequential involvement of the transcriptome in the pathogenesis of PD, as well as the fact that changes at the transcriptome level of the processes of transport and mitochondrial biogenesis can play an important role in neurodegeneration in PD at an early stage.

scholarly journals Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Benedict Tanudjojo ◽  
Samiha S. Shaikh ◽  
Alexis Fenyi ◽  
Luc Bousset ◽  
Devika Agarwal ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Multiple System Atrophy ◽  
Neuronal Death ◽  
Dopaminergic Neurons ◽  
De Novo ◽  
Dependent Manner ◽  
Human Neurons ◽  
Phenotypic Manifestation ◽  
Induced Aggregation

Abstractα-Synuclein is critical in the pathogenesis of Parkinson’s disease and related disorders, yet it remains unclear how its aggregation causes degeneration of human dopaminergic neurons. In this study, we induced α-synuclein aggregation in human iPSC-derived dopaminergic neurons using fibrils generated de novo or amplified in the presence of brain homogenates from Parkinson’s disease or multiple system atrophy. Increased α-synuclein monomer levels promote seeded aggregation in a dose and time-dependent manner, which is associated with a further increase in α-synuclein gene expression. Progressive neuronal death is observed with brain-amplified fibrils and reversed by reduction of intraneuronal α-synuclein abundance. We identified 56 proteins differentially interacting with aggregates triggered by brain-amplified fibrils, including evasion of Parkinson’s disease-associated deglycase DJ-1. Knockout of DJ-1 in iPSC-derived dopaminergic neurons enhance fibril-induced aggregation and neuronal death. Taken together, our results show that the toxicity of α-synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our study demonstrates how Parkinson’s disease-associated genes influence the phenotypic manifestation of strains in human neurons.

scholarly journals Holistic Metabolomic Laboratory-Developed Test (LDT): Development and Use for the Diagnosis of Early-Stage Parkinson’s Disease

Metabolites ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 14
Author(s):  
Petr G. Lokhov ◽  
Dmitry L. Maslov ◽  
Steven Lichtenberg ◽  
Oxana P. Trifonova ◽  
Elena E. Balashova
Keyword(s):  
Parkinson’S Disease ◽  
Molecular Weight ◽  
Parkinson's Disease ◽  
High Resolution Mass Spectrometry ◽  
Early Stage ◽  
Disease Diagnosis ◽  
The Body ◽  
Low Molecular Weight ◽  
Low Molecular Weight Compounds

A laboratory-developed test (LDT) is a type of in vitro diagnostic test that is developed and used within a single laboratory. The holistic metabolomic LDT integrating the currently available data on human metabolic pathways, changes in the concentrations of low-molecular-weight compounds in the human blood during diseases and other conditions, and their prevalent location in the body was developed. That is, the LDT uses all of the accumulated metabolic data relevant for disease diagnosis and high-resolution mass spectrometry with data processing by in-house software. In this study, the LDT was applied to diagnose early-stage Parkinson’s disease (PD), which currently lacks available laboratory tests. The use of the LDT for blood plasma samples confirmed its ability for such diagnostics with 73% accuracy. The diagnosis was based on relevant data, such as the detection of overrepresented metabolite sets associated with PD and other neurodegenerative diseases. Additionally, the ability of the LDT to detect normal composition of low-molecular-weight compounds in blood was demonstrated, thus providing a definition of healthy at the molecular level. This LDT approach as a screening tool can be used for the further widespread testing for other diseases, since ‘omics’ tests, to which the metabolomic LDT belongs, cover a variety of them.

Development of standardized regression-based formulas to assess meaningful cognitive change in early Parkinson’s disease

2020 ◽  
Author(s):  
Hannah L Combs ◽  
Kate A Wyman-Chick ◽  
Lauren O Erickson ◽  
Michele K York
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Test Scores ◽  
Prediction Models ◽  
Early Stage ◽  
Cognitive Change ◽  
Cognitive Test ◽  
Healthy Controls ◽  
Change Over Time ◽  
Over Time

Abstract Objective Longitudinal assessment of cognitive and emotional functioning in patients with Parkinson’s disease (PD) is helpful in tracking progression of the disease, developing treatment plans, evaluating outcomes, and educating patients and families. Determining whether change over time is meaningful in neurodegenerative conditions, such as PD, can be difficult as repeat assessment of neuropsychological functioning is impacted by factors outside of cognitive change. Regression-based prediction formulas are one method by which clinicians and researchers can determine whether an observed change is meaningful. The purpose of the current study was to develop and validate regression-based prediction models of cognitive and emotional test scores for participants with early-stage idiopathic PD and healthy controls (HC) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). Methods Participants with de novo PD and HC were identified retrospectively from the PPMI archival database. Data from baseline testing and 12-month follow-up were utilized in this study. In total, 688 total participants were included in the present study (NPD = 508; NHC = 185). Subjects from both groups were randomly divided into development (70%) and validation (30%) subsets. Results Early-stage idiopathic PD patients and healthy controls were similar at baseline. Regression-based models were developed for all cognitive and self-report mood measures within both populations. Within the validation subset, the predicted and observed cognitive test scores did not significantly differ, except for semantic fluency. Conclusions The prediction models can serve as useful tools for researchers and clinicians to study clinically meaningful cognitive and mood change over time in PD.

scholarly journals Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

2021 ◽  
Vol 22 (12) ◽  
pp. 6277
Author(s):  
Joanna A. Motyl ◽  
Joanna B. Strosznajder ◽  
Agnieszka Wencel ◽  
Robert P. Strosznajder
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Fate ◽  
Neuronal Death ◽  
Neurological Diseases ◽  
Alpha Synuclein ◽  
Lipid Mediator ◽  
Cell Defense ◽  
Promising Therapeutic Approach ◽  
S1p Receptor

Molecular studies have provided increasing evidence that Parkinson’s disease (PD) is a protein conformational disease, where the spread of alpha-synuclein (ASN) pathology along the neuraxis correlates with clinical disease outcome. Pathogenic forms of ASN evoke oxidative stress (OS), neuroinflammation, and protein alterations in neighboring cells, thereby intensifying ASN toxicity, neurodegeneration, and neuronal death. A number of evidence suggest that homeostasis between bioactive sphingolipids with opposing function—e.g., sphingosine-1-phosphate (S1P) and ceramide—is essential in pro-survival signaling and cell defense against OS. In contrast, imbalance of the “sphingolipid biostat” favoring pro-oxidative/pro-apoptotic ceramide-mediated changes have been indicated in PD and other neurodegenerative disorders. Therefore, we focused on the role of sphingolipid alterations in ASN burden, as well as in a vast range of its neurotoxic effects. Sphingolipid homeostasis is principally directed by sphingosine kinases (SphKs), which synthesize S1P—a potent lipid mediator regulating cell fate and inflammatory response—making SphK/S1P signaling an essential pharmacological target. A growing number of studies have shown that S1P receptor modulators, and agonists are promising protectants in several neurological diseases. This review demonstrates the relationship between ASN toxicity and alteration of SphK-dependent S1P signaling in OS, neuroinflammation, and neuronal death. Moreover, we discuss the S1P receptor-mediated pathways as a novel promising therapeutic approach in PD.

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