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 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 Effects of Aging in the Striatum and Substantia Nigra of a Parkinson’s Disease Animal Model

2018 ◽  
Vol 46 (3) ◽  
pp. 348-358 ◽  
Author(s):  
Rodrigo Portes Ureshino ◽  
Angelica Jardim Costa ◽  
Adolfo Garcia Erustes ◽  
Gustavo José da Silva Pereira ◽  
Rita Sinigaglia-Coimbra ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Substantia Nigra Pars Compacta ◽  
Mobility Impairment ◽  
Ultrastructural Alterations ◽  
Age Related ◽  
Effects Of Aging ◽  
Species Production

Aging is a multifactorial process associated with functional deficits, and the brain is more prone to developing chronic degenerative diseases such as Parkinson’s disease. Several groups have tried to correlate the age-related ultrastructural alterations to the neurodegeneration process using in vivo pharmacological models, but due to the limitations of the animal models, particularly in aged animals, the results are difficult to interpret. In this work, we investigated neurodegeneration induced by rotenone, as a pharmacological model of Parkinson’s disease, in both young and aged Wistar rats. We assessed animal mobility, tyrosine hydroxylase staining in the substantia nigra pars compacta (SNpc), and TdT-mediated dUTP-biotin nick end labeling-positive nuclei and reactive oxygen species production in the striatum. Interestingly, the mobility impairment, dopaminergic neuron loss, and elevated number of apoptotic nuclei in the striatum of aged control rats were similar to young rotenone-treated animals. Moreover, we observed many ultrastructural alterations, such as swollen mitochondria in the striatum, and massive lipofuscin deposits in the SNpc of the aged rotenone-treated animals. We conclude that the rotenone model can be employed to explore age-related alterations in the ontogeny that can increase vulnerability in the striatum and SNpc, which may contribute to Parkinson’s disease pathogenesis.

scholarly journals To be or not to be pink(1): contradictory findings in an animal model for Parkinson’s disease

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Ria de Haas ◽  
Lisa C M W Heltzel ◽  
Denise Tax ◽  
Petra van den Broek ◽  
Hilbert Steenbreker ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
In Vivo Microdialysis ◽  
Substantia Nigra Pars Compacta ◽  
Laboratory Animals ◽  
Motor Deficits

Abstract The PTEN-induced putative kinase 1 knockout rat (Pink1−/−) is marketed as an established model for Parkinson’s disease, characterized by development of motor deficits and progressive degeneration of half the dopaminergic neurons in the substantia nigra pars compacta by 8 months of age. In this study, we address our concerns about the reproducibility of the Pink1−/− rat model. We evaluated behavioural function, number of substantia nigra dopaminergic neurons and extracellular striatal dopamine concentrations by in vivo microdialysis. Strikingly, we and others failed to observe any loss of dopaminergic neurons in 8-month-old male Pink1−/− rats. To understand this variability, we compared key experimental parameters from the different studies and provide explanations for contradictory findings. Although Pink1−/− rats developed behavioural deficits, these could not be attributed to nigrostriatal degeneration as there was no loss of dopaminergic neurons in the substantia nigra and no changes in neurotransmitter levels in the striatum. To maximize the benefit of Parkinson’s disease research and limit the unnecessary use of laboratory animals, it is essential that the research community is aware of the limits of this animal model. Additional research is needed to identify reasons for inconsistency between Pink1−/− rat colonies and why degeneration in the substantia nigra is not consistent.

scholarly journals Reliability of Dopamine Transporter PET Measurements with [18F]FE-PE2I in patients with Parkinson's Disease

2020 ◽  
Author(s):  
Vera S. Kerstens ◽  
Patrik Fazio ◽  
Mathias Sundgren ◽  
Granville J. Matheson ◽  
Erika Franzén ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopamine Transporter ◽  
Radioligand Binding ◽  
Binding Potential ◽  
Measurement Variability ◽  
Power Calculations ◽  
Affected Side ◽  
Progression Marker

Abstract Background. Reliable quantification of dopamine transporter (DAT), a biomarker for Parkinson’s disease (PD), is essential for diagnostic purposes as well as for evaluation of potential disease-modifying treatment. Due to degeneration of dopaminergic neurons and thus lower expected radioligand binding to DAT, higher measurement variability in PD patients might be expected than earlier reproducibility results in healthy controls. Therefore, we aimed to examine the test-retest properties of [18F]FE-PE2I-PET in PD patients. Methods. Nine patients with PD (Hoehn & Yahr stage < 3) were included (men/women: 6/3; mean age 65.2±6.8y). Each patient underwent two [18F]FE-PE2I-PET measurements within 7–28 days. The outcome measure was non-displaceable binding potential generated using wavelet-aided parametric imaging with cerebellum as reference region. We assessed test-retest performance using estimates of reliability and repeatability. Regions for primary analysis were caudate, putamen, ventral striatum, and substantia nigra. Exploratory analysis was performed for functional subdivisions of the striatum. We also compared the more vs. less-affected side. Results. [18F]FE-PE2I showed absolute variability estimates of 5.3–7.6% in striatal regions and 11% in substantia nigra, and ICCs of 0.74—0.97 (median: 0.91). The absolute variability for functional striatal subdivisions was 6.0–9.6% and ICCs of 0.76–0.91 (median: 0.91). The less affected substantia nigra exhibited greater consistency than the more affected side. According to power calculations based on the current sample size, DAT changes of 5–11% in the striatum and 28% in the substantia nigra can be detected with a power of 0.8 (p<0.0125).Conclusion. DAT-PET measurements with [18F]FE-PE2I in PD patients showed good repeatability and reliability. The slightly lower reliability in the substantia nigra in patients may be explained by lower DAT density and smaller anatomical size. Power calculations suggest that [18F]FE-PE2I PET of DAT is a suitable disease progression marker in PD. Trial registration number: EudraCT 2017-003327-29 Keywords: reliability, test-retest, [18F]FE-PE2I, dopamine transporter, Parkinson’s disease

scholarly journals Alteration in the Cerebrospinal Fluid Lipidome in Parkinson’s Disease: A Post-Mortem Pilot Study

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 491
Author(s):  
Joaquín Fernández-Irigoyen ◽  
Paz Cartas-Cejudo ◽  
Marta Iruarrizaga-Lejarreta ◽  
Enrique Santamaría
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cerebrospinal Fluid ◽  
Ultra Performance Liquid Chromatography ◽  
Small Population ◽  
Control Group ◽  
Post Mortem ◽  
Cellular Models ◽  
Flight Mass Spectrometry ◽  
Lipid Species

Lipid metabolism is clearly associated to Parkinson’s disease (PD). Although lipid homeostasis has been widely studied in multiple animal and cellular models, as well as in blood derived from PD individuals, the cerebrospinal fluid (CSF) lipidomic profile in PD remains largely unexplored. In this study, we characterized the post-mortem CSF lipidomic imbalance between neurologically intact controls (n = 10) and PD subjects (n = 20). The combination of dual extraction with ultra-performance liquid chromatography-electrospray ionization quadrupole-time-of-flight mass spectrometry (UPLC-ESI-qToF-MS/MS) allowed for the monitoring of 257 lipid species across all samples. Complementary multivariate and univariate data analysis identified that glycerolipids (mono-, di-, and triacylglycerides), saturated and mono/polyunsaturated fatty acids, primary fatty amides, glycerophospholipids (phosphatidylcholines, phosphatidylethanolamines), sphingolipids (ceramides, sphingomyelins), N-acylethanolamines and sterol lipids (cholesteryl esters, steroids) were significantly increased in the CSF of PD compared to the control group. Interestingly, CSF lipid dyshomeostasis differed depending on neuropathological staging and disease duration. These results, despite the limitation of being obtained in a small population, suggest extensive CSF lipid remodeling in PD, shedding new light on the deployment of CSF lipidomics as a promising tool to identify potential lipid markers as well as discriminatory lipid species between PD and other atypical parkinsonisms.

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 Combined knockout of Lrrk2 and Rab29 does not result in behavioral abnormalities in vivo

2020 ◽  
Author(s):  
Melissa Conti Mazza ◽  
Victoria Nguyen ◽  
Alexandra Beilina ◽  
Jinhui Ding ◽  
Mark R. Cookson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Association Studies ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Genome Wide Association Studies ◽  
Double Knockout ◽  
Knockout Mouse Model

AbstractCoding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson’s disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, leading to the suggestion that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, here we generated a double knockout mouse model and determined whether there are any consequences on brain function with aging. From a battery of motor and non-motor behavioral tests, we noted only that 18-24 month Rab29-/- and double (Lrrk2-/-/Rab29-/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in number of substantia nigra pars compacta (SNc) dopamine neurons or in tyrosine hydroxylase levels in the SNc and striatum, which might reflect a PD-like pathology. These results suggest that depletion of both Lrrk2 and Rab29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans.Significance statementGenetic variation in LRRK2 that result in elevated kinase activity can cause Parkinson’s disease (PD), suggesting LRRK2 inhibition as a therapeutic strategy. RAB29, a substrate of LRRK2, has also been associated with increased PD risk. Evidence exists for an interactive relationship between LRRK2 and RAB29. Mouse models lacking either LRRK2 or RAB29 do not show brain pathologies. We hypothesized that the loss of both targets would result in additive effects across in vivo and post-mortem assessments in aging mice. We found that loss of both LRRK2 and RAB29 did not result in significant behavioral deficits or dopamine neuron loss. This evidence suggests that chronic inhibition of this pathway should be tolerated clinically.

scholarly journals p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Jialong Chen ◽  
Kanmin Mao ◽  
Honglin Yu ◽  
Yue Wen ◽  
Hua She ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nlrp3 Inflammasome ◽  
Dopaminergic Neurons ◽  
Microglia Activation ◽  
Microglial Cells ◽  
Substantia Nigra Pars Compacta ◽  
Mice Model ◽  
Chaperone Mediated Autophagy

Abstract Background Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), accompanied by accumulation of α-synuclein, chronic neuroinflammation and autophagy dysfunction. Previous studies suggested that misfolded α-synuclein induces the inflammatory response and autophagy dysfunction in microglial cells. The NLRP3 inflammasome signaling pathway plays a crucial role in the neuroinflammatory process in the central nervous system. However, the relationship between autophagy deficiency and NLRP3 activation induced by α-synuclein accumulation is not well understood. Methods Through immunoblotting, immunocytochemistry, immunofluorescence, flow cytometry, ELISA and behavioral tests, we investigated the role of p38-TFEB-NLRP3 signaling pathways on neuroinflammation in the α-synuclein A53T PD models. Results Our results showed that increased protein levels of NLRP3, ASC, and caspase-1 in the α-synuclein A53T PD models. P38 is activated by overexpression of α-synuclein A53T mutant, which inhibited the master transcriptional activator of autophagy TFEB. And we found that NLRP3 was degraded by chaperone-mediated autophagy (CMA) in microglial cells. Furthermore, p38-TFEB pathways inhibited CMA-mediated NLRP3 degradation in Parkinson's disease. Inhibition of p38 had a protective effect on Parkinson's disease model via suppressing the activation of NLRP3 inflammasome pathway. Moreover, both p38 inhibitor SB203580 and NLRP3 inhibitor MCC950 not only prevented neurodegeneration in vivo, but also alleviated movement impairment in α-synuclein A53T-tg mice model of Parkinson’s disease. Conclusion Our research reveals p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease, which could be a potential therapeutic strategy for PD. Graphical abstract p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease. In this model, p38 activates NLRP3 inflammasome via inhibiting TFEB in microglia. TFEB signaling negatively regulates NLRP3 inflammasome through increasing LAMP2A expression, which binds to NLRP3 and promotes its degradation via chaperone-mediated autophagy (CMA). NLRP3-mediated microglial activation promotes the death of dopaminergic neurons.

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