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.

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 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 Correcting differential gene expression analysis for cyto-architectural alterations in substantia nigra of Parkinson's disease patients reveals known and potential novel disease-associated genes and pathways

2021 ◽  
Author(s):  
Federico Ferraro ◽  
Christina Fevga ◽  
Vincenzo Bonifati ◽  
Wim Mandemakers ◽  
Ahmed Mahfouz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Gene Expression Profiles ◽  
Substantia Nigra Pars Compacta ◽  
Ammonium Transport ◽  
Protein Interaction Data

Several studies have analyzed gene expression profiles in the substantia nigra to better understand the pathological mechanisms causing Parkinson's disease (PD). However, the concordance between the identified gene signatures in these individual studies was generally low. This might be caused by a change in cell type composition as loss of dopaminergic neurons in the substantia nigra pars compacta is a hallmark of PD. Through an extensive meta-analysis of nine previously published microarray studies, we demonstrated that a big proportion of the detected differentially expressed genes was indeed caused by cyto-architectural alterations due to the heterogeneity in the neurodegenerative stage and/or technical artifacts. After correcting for cell composition, we identified a common signature that deregulated the previously unreported ammonium transport, as well as known biological processes including bioenergetic pathways, response to proteotoxic stress, and immune response. By integrating with protein-interaction data, we shortlisted a set of key genes, such as LRRK2, PINK1, and PRKN known to be related to PD; others with compelling evidence for their role in neurodegeneration, such as GSK3β, WWOX, and VPC; as well as novel potential players in the PD pathogenesis, including NTRK1, TRIM25, ELAVL1. Together, these data showed the importance of accounting for cyto-architecture in these analyses and highlight the contribution of multiple cell types and novel processes to PD pathology providing potential new targets for drug development.

scholarly journals Gender biased neuroprotective effect of Transferrin Receptor 2 deletion in multiple models of Parkinson’s disease

2020 ◽  
Author(s):  
Chiara Milanese ◽  
Sylvia Gabriels ◽  
Sander Barnhoorn ◽  
Silvia Cerri ◽  
Ayse Ulusoy ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Iron Overload ◽  
Transferrin Receptor ◽  
Dopaminergic Neurons ◽  
Iron Homeostasis ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Transferrin Receptor 2

AbstractAlterations in the metabolism of iron and its accumulation in the substantia nigra pars compacta accompany the pathogenesis of Parkinson’s disease (PD). Changes in iron homeostasis also occur during aging, which constitutes a PD major risk factor. As such, mitigation of iron overload via chelation strategies has been considered a plausible disease modifying approach. Iron chelation, however, is imperfect because of general undesired side effects and lack of specificity; more effective approaches would rely on targeting distinctive pathways responsible for iron overload in brain regions relevant to PD and, in particular, the substantia nigra. We have previously demonstrated that the Transferrin/Transferrin Receptor 2 (TfR2) iron import mechanism functions in nigral dopaminergic neurons, is perturbed in PD models and patients, and therefore constitutes a potential therapeutic target to halt iron accumulation. To validate this hypothesis, we generated mice with targeted deletion of TfR2 in dopaminergic neurons. In these animals, we modeled PD with multiple approaches, based either on neurotoxin exposure or alpha-synuclein proteotoxic mechanisms. We found that TfR2 deletion can provide neuroprotection against dopaminergic degeneration, and against PD- and aging-related iron overload. The effects, however, were significantly more pronounced in females rather than in males. Our data indicate that the TfR2 iron import pathway represents an amenable strategy to hamper PD progression. Data also suggest, however, that therapeutic strategies targeting TfR2 should consider a potential sexual dimorphism in neuroprotective response.

scholarly journals Pesticides and Parkinson’s Disease

2001 ◽  
Vol 1 ◽  
pp. 207-208 ◽  
Author(s):  
Todd B. Sherer ◽  
Ranjita Betarbet ◽  
J. Timothy Greenamyre
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Selective Death ◽  
Underlying Mechanisms ◽  
Common Neurodegenerative Disorder

Parkinson’s disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies [1-2]. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear.

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 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.

scholarly journals Correcting Differential Gene Expression Analysis for Cyto—Architectural Alterations in Substantia Nigra of Parkinson’s Disease Patients Reveals Known and Potential Novel Disease—Associated Genes and Pathways

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 198
Author(s):  
Federico Ferraro ◽  
Christina Fevga ◽  
Vincenzo Bonifati ◽  
Wim Mandemakers ◽  
Ahmed Mahfouz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Gene Expression Profiles ◽  
Substantia Nigra Pars Compacta ◽  
Ammonium Transport ◽  
Protein Interaction Data

Several studies have analyzed gene expression profiles in the substantia nigra to better understand the pathological mechanisms causing Parkinson’s disease (PD). However, the concordance between the identified gene signatures in these individual studies was generally low. This might have been caused by a change in cell type composition as loss of dopaminergic neurons in the substantia nigra pars compacta is a hallmark of PD. Through an extensive meta-analysis of nine previously published microarray studies, we demonstrated that a big proportion of the detected differentially expressed genes was indeed caused by cyto-architectural alterations due to the heterogeneity in the neurodegenerative stage and/or technical artefacts. After correcting for cell composition, we identified a common signature that deregulated the previously unreported ammonium transport, as well as known biological processes such as bioenergetic pathways, response to proteotoxic stress, and immune response. By integrating with protein interaction data, we shortlisted a set of key genes, such as LRRK2, PINK1, PRKN, and FBXO7, known to be related to PD, others with compelling evidence for their role in neurodegeneration, such as GSK3β, WWOX, and VPC, and novel potential players in the PD pathogenesis. Together, these data show the importance of accounting for cyto-architecture in these analyses and highlight the contribution of multiple cell types and novel processes to PD pathology, providing potential new targets for drug development.

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