scholarly journals Polyomic Analyses of Dopaminergic Neurons Isolated From Human Substantia Nigra in Parkinson’s Disease: An Exploratory Study.

2021 ◽  
Author(s):  
Affif ZACCARIA ◽  
Paola Antinori Malaspina ◽  
Virginie Licker ◽  
Enikö Kovari ◽  
Johannes A Lobrinus ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Protein Expression ◽  
Differential Expression ◽  
Exploratory Study ◽  
Substantia Nigra Pars Compacta ◽  
Control Group ◽  
Gene And Protein Expression ◽  
And Control

Abstract Background Dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) selectively and progressively degenerate in Parkinson’s disease (PD). Until now, molecular analyses of DA neurons in PD have been limited to genomic and transcriptomic approaches, whereas, to the best of our knowledge, no proteomic or combined polyomic study examining the protein profile of these neurons, is currently available. Methods In this exploratory study, we used laser microdissection to extract DA neurons from 10 human SNpc samples obtained at autopsy in PD patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nano-LC-MS/MS, respectively, and the differential expression between the PD and control group was assessed. Results Qualitative analyses confirmed that the microdissection protocol preserves the integrity of our samples and offers access to specific molecular pathways. This polyomic analysis highlighted differential expression of 52 genes and 33 proteins, including molecules of interest already known to be dysregulated in PD, such as LRP2, PNMT, CXCR4, MAOA and CBLN1 genes, or the Aldehyde dehydrogenase 1 protein. On the other hand, despite the same samples were used for both analyses, correlation between RNA and protein expression was low, as exemplified by the CST3 gene encoding for the cystatin C protein. Conclusion This is the first exploratory study analyzing both gene and protein expression of LMD-dissected DA neurons from SNpc in PD. Although correlation between RNA and protein expressions was limited, this polyomic study provides an extensive and integrated overview of molecular changes identified in the PD SNpc and may offer novel insights into specific pathological processes at work in PD degeneration.

scholarly journals Multiomic Analyses of Dopaminergic Neurons Isolated from Human Substantia Nigra in Parkinson’s Disease: A Descriptive and Exploratory Study

2021 ◽  
Author(s):  
Affif Zaccaria ◽  
Paola Antinori ◽  
Virginie Licker ◽  
Enikö Kövari ◽  
Johannes A. Lobrinus ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Protein Expression ◽  
Differential Expression ◽  
Dopaminergic Neurons ◽  
Exploratory Study ◽  
Control Group ◽  
Gene And Protein Expression ◽  
And Control

AbstractDopaminergic neurons (DA) of the substantia nigra pars compacta (SNpc) selectively and progressively degenerate in Parkinson’s disease (PD). Until now, molecular analyses of DA in PD have been limited to genomic or transcriptomic approaches, whereas, to the best of our knowledge, no proteomic or combined multiomic study examining the protein profile of these neurons is currently available. In this exploratory study, we used laser capture microdissection to extract regions from DA in 10 human SNpc obtained at autopsy in PD patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nanoliquid chromatography–mass spectrometry, respectively, and the differential expression between PD and control group was assessed. Qualitative analyses confirmed that the microdissection protocol preserves the integrity of our samples and offers access to specific molecular pathways. This multiomic analysis highlighted differential expression of 52 genes and 33 proteins, including molecules of interest already known to be dysregulated in PD, such as LRP2, PNMT, CXCR4, MAOA and CBLN1 genes, or the Aldehyde dehydrogenase 1 protein. On the other hand, despite the same samples were used for both analyses, correlation between RNA and protein expression was low, as exemplified by the CST3 gene encoding for the cystatin C protein. This is the first exploratory study analyzing both gene and protein expression of laser-dissected neuronal parts from SNpc in PD. Data are available via ProteomeXchange with identifier PXD024748 and via GEO with identifier GSE 169755.

Polyomic analyses of dopaminergic neurons isolated from human substantia nigra in Parkinson’s disease: An exploratory study.

2021 ◽  
Author(s):  
Affif ZACCARIA ◽  
Paola Antinori Malaspina ◽  
Virginie Licker ◽  
Enikö Kovari ◽  
Johannes A Lobrinus ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Protein Expression ◽  
Differential Expression ◽  
Dopaminergic Neurons ◽  
Exploratory Study ◽  
Substantia Nigra Pars Compacta ◽  
Gene And Protein Expression ◽  
And Control

Abstract Dopaminergic neurons of the substantia nigra pars compacta selectively and progressively degenerate in Parkinson’s disease. Until now, molecular analyses of dopaminergic neurons in PD have been limited to genomic and transcriptomic approaches, whereas, to the best of our knowledge, no proteomic or combined polyomic study examining the protein profile of these neurons, is currently available. In this exploratory study, we used laser microdissection to extract dopaminergic neurons from 10 human SNpc samples obtained at autopsy in Parkinson’s disease patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nano-LC-MS/MS, respectively, and the differential expression between Parkinson’s disease and control group was assessed. Qualitative analyses confirmed that the microdissection protocol preserves the integrity of our samples and offers access to specific molecular pathways. This polyomic analysis highlighted differential expression of 52 genes and 33 proteins, including molecules of interest already known to be dysregulated in Parkinson’s disease, such as LRP2 , PNMT , CXCR4 , MAOA and CBLN1 genes, or the Aldehyde dehydrogenase 1 protein. On the other hand, despite the same samples were used for both analyses, correlation between RNA and protein expression was low, as exemplified by the CST3 gene encoding for the cystatin C protein. This is the first exploratory study analyzing both gene and protein expression of LMD-dissected neurons from substantia nigra pars compacta in Parkinson’s disease. Data are available via ProteomeXchange with identifier PXD024748 and via GEO with identifier GSE 169755.

scholarly journals Relationship between neuromelanin and dopamine terminals within the Parkinson’s nigrostriatal system

Brain ◽  
2019 ◽  
Vol 142 (7) ◽  
pp. 2023-2036 ◽  
Author(s):  
Antonio Martín-Bastida ◽  
Nicholas P Lao-Kaim ◽  
Andreas Antonios Roussakis ◽  
Graham E Searle ◽  
Yue Xing ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopamine Transporter ◽  
Substantia Nigra Pars Compacta ◽  
Control Group ◽  
Post Mortem ◽  
Significant Relationships ◽  
Affected Side

Abstract Parkinson’s disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson’s disease. Fifteen healthy control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson’s disease subjects displayed reduced neuromelanin levels in the ventral (−30 ± 28%) and dorsal tiers (−21 ± 24%) as compared to the control group [F(1,43) = 11.95, P = 0.001]. Within the Parkinson’s disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 4.21, P = 0.049]. Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson’s disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.

scholarly journals MicroRNA Dysregulation in Parkinson’s Disease: A Narrative Review

2021 ◽  
Vol 15 ◽  
Author(s):  
Yong Hui Nies ◽  
Nor Haliza Mohamad Najib ◽  
Wei Ling Lim ◽  
Mohd Amir Kamaruzzaman ◽  
Mohamad Fairuz Yahaya ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Expression Profiles ◽  
Lewy Bodies ◽  
Complete Recovery ◽  
Substantia Nigra Pars Compacta ◽  
Dopamine Depletion ◽  
Gene And Protein Expression

Parkinson’s disease (PD) is a severely debilitating neurodegenerative disease, affecting the motor system, leading to resting tremor, cogwheel rigidity, bradykinesia, walking and gait difficulties, and postural instability. The severe loss of dopaminergic neurons in the substantia nigra pars compacta causes striatal dopamine deficiency and the presence of Lewy bodies indicates a pathological hallmark of PD. Although the current treatment of PD aims to preserve dopaminergic neurons or to replace dopamine depletion in the brain, it is notable that complete recovery from the disease is yet to be achieved. Given the complexity and multisystem effects of PD, the underlying mechanisms of PD pathogenesis are yet to be elucidated. The advancement of medical technologies has given some insights in understanding the mechanism and potential treatment of PD with a special interest in the role of microRNAs (miRNAs) to unravel the pathophysiology of PD. In PD patients, it was found that striatal brain tissue and dopaminergic neurons from the substantia nigra demonstrated dysregulated miRNAs expression profiles. Hence, dysregulation of miRNAs may contribute to the pathogenesis of PD through modulation of PD-associated gene and protein expression. This review will discuss recent findings on PD-associated miRNAs dysregulation, from the regulation of PD-associated genes, dopaminergic neuron survival, α-synuclein-induced inflammation and circulating miRNAs. The next section of this review also provides an update on the potential uses of miRNAs as diagnostic biomarkers and therapeutic tools for PD.

scholarly journals Study of cognitive impairment and genetic polymorphism of SLC41A1 (rs11240569 allele) in Parkinson’s disease in Upper Egypt: case-control study

2021 ◽  
Vol 57 (1) ◽  
Author(s):  
Hamdy N. El-Tallawy ◽  
Tahia H. Saleem ◽  
Wafaa M. Farghaly ◽  
Heba Mohamed Saad Eldien ◽  
Ashraf Khodaery ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Case Control Study ◽  
Case Control ◽  
Control Group ◽  
Motor Symptoms ◽  
And Control ◽  
Non Motor Symptoms ◽  
Control Study

Abstract Background Parkinson’s disease is one of the neurodegenerative disorders that is caused by genetic and environmental factors or interaction between them. Solute carrier family 41 member 1 within the PARK16 locus has been reported to be associated with Parkinson’s disease. Cognitive impairment is one of the non-motor symptoms that is considered a challenge in Parkinson’s disease patients. This study aimed to investigate the association of rs11240569 polymorphism; a synonymous coding variant in SLC41A1 in Parkinson’s disease patients in addition to the assessment of cognitive impairment in those patients. Results In a case -control study, rs11240569 single nucleotide polymorphisms in SLC41A1, genes were genotyped in 48 Parkinson’s disease patients and 48 controls. Motor and non-motor performance in Parkinson's disease patients were assessed by using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). The genotype and allele frequencies were compared between the two groups and revealed no significant differences between case and control groups for rs11240569 in SLC41A1 gene with P value .523 and .54, respectively. Cognition was evaluated and showed the mean ± standard deviation (SD) of WAIS score of PD patients 80.4 ± 9.13 and the range was from 61 to 105, in addition to MMSE that showed mean ± SD 21.96 ± 3.8. Conclusion Genetic testing of the present study showed that rs11240569 polymorphism of SLC41A1 gene has no significant differences in distributions of alleles and genotypes between cases and control group, in addition to cognitive impairment that is present in a large proportion of PD patients and in addition to the strong correlation between cognitive impairment and motor and non-motor symptoms progression.

Mildronate as a Regulator of Protein Expression in a Rat Model of Parkinson’s Disease

Medicina ◽  
2011 ◽  
Vol 47 (10) ◽  
pp. 79 ◽  
Author(s):  
Sergejs Isajevs ◽  
Darja Isajeva ◽  
Ulrika Beitnere ◽  
Baiba Jansone ◽  
Ivars Kalvinsh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Growth Factor ◽  
Substantia Nigra ◽  
Rat Model ◽  
Control Group ◽  
Western Blot Assay ◽  
Neural Cell Adhesion ◽  
6 Hydroxydopamine ◽  
Cardioprotective Drug

Background. Mildronate (3-[2,2,2-trimethylhydrazinium] propionate dihydrate) traditionally is a well-known cardioprotective drug. However, our recent studies convincingly demonstrated its neuroprotective properties. The aim of the present study was to evaluate the influence of mildronate on the expression of proteins that are involved in the differentiation and survival of the nigrostriatal dopaminergic neurons in the rat model of Parkinson’s disease (PD). The following biomarkers were used: heat shock protein 70 (Hsp70, a molecular chaperone), glial cell line-derived nerve growth factor (GDNF, a growth factor promoting neuronal differentiation, regeneration, and survival), and neural cell adhesion molecule (NCAM). Material and Methods. PD was modeled by 6-hydroxydopamine (6-OHDA) unilateral intrastriatal injection in rats. Mildronate was administered at doses of 10, 20, and 50 mg/kg for 2 weeks intraperitoneally before 6-OHDA injection. Rat brains were dissected on day 28 after discontinuation of mildronate injections. The expression of biomarkers was assessed immunohistochemically and by Western blot assay. Results. 6-OHDA decreased the expression of Hsp70 and GDNF in the lesioned striatum and substantia nigra, whereas in mildronate-pretreated (20 and 50 mg/kg) rats, the expression of Hsp70 and GDNF was close to the control group values. NCAM expression also was decreased by 6-OHDA in the striatum and it was totally protected by mildronate at a dose of 50 mg/kg. In contrast, in the substantia nigra, 6-OHDA increased the expression of NCAM, while mildronate pretreatment (20 and 50 mg/kg) reversed the 6-OHDA-induced overexpression of NCAM close to the control values. Conclusion. The obtained data showed that mildronate was capable to regulate the expression of proteins that play a role in the homeostasis of neuro-glial processes.

scholarly journals Substantia nigra ferric overload and neuromelanin loss in Parkinson's disease measured with 7T MRI

2021 ◽  
Author(s):  
Catarina Rua ◽  
Claire O'Callaghan ◽  
Rong Ye ◽  
Frank Hubert Hezemans ◽  
Luca Passamonti ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
High Resolution ◽  
Substantia Nigra ◽  
Clinical Severity ◽  
7 Tesla ◽  
Control Group ◽  
Healthy Controls ◽  
Iron Loading ◽  
Weighted Sequence

Background: Vulnerability of the substantia nigra dopaminergic neurons in Parkinson's disease is associated with ferric overload, leading to neurodegeneration with cognitive and motor decline. Here, we quantify iron and neuromelanin-related markers in vivo using ultra-high field 7-Tesla MRI, and examine the clinical correlates of these imaging assessments. Methods: Twenty-five people with mild-to-moderate Parkinson's disease and twenty-six healthy controls underwent high-resolution imaging at 7-Tesla with a T2*-weighted sequence (measuring susceptibility-χ and R2*, sensitive to iron) and a magnetization transfer-weighted sequence (MT-w, sensitive to neuromelanin). From an independent control group (N=29), we created study-specific regions-of-interest for five neuromelanin- and/or iron-rich subregions within the substantia nigra. Mean R2*, susceptibility-χ and their ratio, as well as the MT-w contrast-to-noise ratio (MT-CNR) were extracted from these regions and compared between groups. We then tested the relationships between these imaging metrics and clinical severity. Results: People with Parkinson's disease showed a significant ~50% reduction in MT-CNR compared to healthy controls. They also showed a 1.2-fold increase in ferric iron loading (elevation of the ΔR2*/Δχ ratio from 0.19±0.058ms/ppm to 0.22±0.059ms/ppm) in an area of the substantia nigra identified as having both high neuromelanin and susceptibility MRI signal in healthy controls. In this region, the ferric-to-ferrous iron loading was associated with disease duration (β=0.0072, pFDR=0.048) and cognitive impairment (β=-0.0115, pFDR=0.048). Conclusions: T2*-weighted and MT-weighted high-resolution 7T imaging markers identified neurochemical consequences of Parkinson's disease, in overlapping but not-identical regions. These changes correlated with non-motor symptoms.

scholarly journals Palmitate and Stearate are Increased in the Plasma in a 6-OHDA Model of Parkinson’s Disease

Metabolites ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 31 ◽  
Author(s):  
Anuri Shah ◽  
Pei Han ◽  
Mung-Yee Wong ◽  
Raymond Chang ◽  
Cristina Legido-Quigley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Stearic Acid ◽  
Palmitic Acid ◽  
Neurodegenerative Disorder ◽  
Motor Dysfunction ◽  
Substantia Nigra Pars Compacta ◽  
Control Group ◽  
Sprague Dawley ◽  
Curative Therapy

Introduction: Parkinson’s disease (PD) is the second most common neurodegenerative disorder, without any widely available curative therapy. Metabolomics is a powerful tool which can be used to identify unexpected pathway-related disease progression and pathophysiological mechanisms. In this study, metabolomics in brain, plasma and liver was investigated in an experimental PD model, to discover small molecules that are associated with dopaminergic cell loss. Methods: Sprague Dawley (SD) rats were injected unilaterally with 6-hydroxydopamine (6-OHDA) or saline for the vehicle control group into the medial forebrain bundle (MFB) to induce loss of dopaminergic neurons in the substantia nigra pars compacta. Plasma, midbrain and liver samples were collected for metabolic profiling. Multivariate and univariate analyses revealed metabolites that were altered in the PD group. Results: In plasma, palmitic acid (q = 3.72 × 10−2, FC = 1.81) and stearic acid (q = 3.84 × 10−2, FC = 2.15), were found to be increased in the PD group. Palmitic acid (q = 3.5 × 10−2) and stearic acid (q = 2.7 × 10−2) correlated with test scores indicative of motor dysfunction. Monopalmitin (q = 4.8 × 10−2, FC = −11.7), monostearin (q = 3.72 × 10−2, FC = −15.1) and myo-inositol (q = 3.81 × 10−2, FC = −3.32), were reduced in the midbrain. The liver did not have altered levels of these molecules. Conclusion: Our results show that saturated free fatty acids, their monoglycerides and myo-inositol metabolism in the midbrain and enteric circulation are associated with 6-OHDA-induced PD pathology.

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