Explorative Combined Lipid and Transcriptomic Profiling of Substantia Nigra and Putamen in Parkinson’s Disease

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons from the substantia nigra (SN) that project to the dorsal striatum (caudate-putamen). To better understand the molecular mechanisms underlying PD, we performed combined lipid profiling and RNA sequencing of SN and putamen samples from PD patients and age-matched controls. SN lipid analysis pointed to a neuroinflammatory component and included elevated levels of the endosomal lipid Bis (Monoacylglycero)Phosphate 42:8, while two of the three depleted putamen lipids were saturated sphingomyelin species. Remarkably, we observed gender-related differences in the SN and putamen lipid profiles. Transcriptome analysis revealed that the top-enriched pathways among the 354 differentially expressed genes (DEGs) in the SN were “protein folding” and “neurotransmitter transport”, and among the 261 DEGs from putamen “synapse organization”. Furthermore, we identified pathways, e.g., “glutamate signaling”, and genes, encoding, e.g., an angiotensin receptor subtype or a proprotein convertase, that have not been previously linked to PD. The identification of 33 genes that were common among the SN and putamen DEGs, which included the α-synuclein paralog β-synuclein, may contribute to the understanding of general PD mechanisms. Thus, our proof-of-concept data highlights new genes, pathways and lipids that have not been explored before in the context of PD.

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Neuroinflammation caused by activated microglia and astrocytes can contribute to the progression of pathogenic damage to substantia nigra neurons, playing a role in Parkinson's disease progression

10.31219/osf.io/ac896 ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Mitochondrial Dysfunction ◽

Dopaminergic Neurons ◽

Molecular Mechanisms ◽

High Energy ◽

Molecular Pathways ◽

Activated Microglia

Parkinson's disease progresses by a number of regionally specific cellular and molecular mechanisms. Furthermore, these pathways interact and have an influence on one another in both normal and pathological conditions. Neuroinflammation caused by activated microglia and astrocytes can contribute to the progression of pathogenic damage to substantia nigra (SN) neurons. Similarly, oxidative stress may be caused by a variety of stressors, such as contaminants in the environment or age-related mitochondrial dysfunction, leading to the production of reactive oxygen species (ROS). Dopamine auto-oxidation is a significant generator of ROS in dopaminergic neurons, resulting in neuronal oxidative stress. The high energy demands of dopaminergic neurons may result in mitochondrial dysfunction and oxidative damage as they age. Because mitophagy clears dysfunctional mitochondria from SN neurons, mutation-related abnormalities in autophagy of defective proteins might allow damaging proteins to accumulate in the cell. Because the effects of aging on these molecular pathways and cellular activities are unknown, further study into these molecular pathways and their connections in normal and sick states will be essential for developing disease-specific therapies.

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Differential Effects of Dopaminergic Therapies on Dorsal and Ventral Striatum in Parkinson's Disease: Implications for Cognitive Function

Parkinson s Disease ◽

10.4061/2011/572743 ◽

2011 ◽

Vol 2011 ◽

pp. 1-18 ◽

Cited By ~ 39

Author(s):

Penny A. MacDonald ◽

Oury Monchi

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Function ◽

Substantia Nigra ◽

Ventral Striatum ◽

Functional Neuroimaging ◽

Dorsal Striatum ◽

Cell Loss ◽

Motor Symptoms ◽

Dopaminergic Therapy

Cognitive abnormalities are a feature of Parkinson's disease (PD). Unlike motor symptoms that are clearly improved by dopaminergic therapy, the effect of dopamine replacement on cognition seems paradoxical. Some cognitive functions are improved whereas others are unaltered or even hindered. Our aim was to understand the effect of dopamine replacement therapy on various aspects of cognition. Whereas dorsal striatum receives dopamine input from the substantia nigra (SN), ventral striatum is innervated by dopamine-producing cells in the ventral tegmental area (VTA). In PD, degeneration of SN is substantially greater than cell loss in VTA and hence dopamine-deficiency is significantly greater in dorsal compared to ventral striatum. We suggest that dopamine supplementation improves functions mediated by dorsal striatum and impairs, or heightens to a pathological degree, operations ascribed to ventral striatum. We consider the extant literature in light of this principle. We also survey the effect of dopamine replacement on functional neuroimaging in PD relating the findings to this framework. This paper highlights the fact that currently, titration of therapy in PD is geared to optimizing dorsal striatum-mediated motor symptoms, at the expense of ventral striatum operations. Increased awareness of contrasting effects of dopamine replacement on dorsal versus ventral striatum functions will lead clinicians to survey a broader range of symptoms in determining optimal therapy, taking into account both those aspects of cognition that will be helped versus those that will be hindered by dopaminergic treatment.

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Mechanisms of Parkinson’s disease-related proteins in mediating secondary brain damage after cerebral ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17694186 ◽

2017 ◽

Vol 37 (6) ◽

pp. 1910-1926 ◽

Cited By ~ 19

Author(s):

TaeHee Kim ◽

Raghu Vemuganti

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Brain Damage ◽

Neuronal Death ◽

Molecular Mechanisms ◽

Time Frame ◽

Cell Death Pathways ◽

Genes Encoding ◽

Aging Populations ◽

Death And Loss

Both Parkinson’s disease (PD) and stroke are debilitating conditions that result in neuronal death and loss of neurological functions. These two conditions predominantly affect aging populations with the deterioration of the quality of life for the patients themselves and a tremendous burden to families. While the neurodegeneration and symptomology of PD develop chronically over the years, post-stroke neuronal death and dysfunction develop rapidly in days. Despite the discrepancy in the pathophysiological time frame and severity, both conditions share common molecular mechanisms that include oxidative stress, mitochondrial dysfunction, inflammation, endoplasmic reticulum stress, and activation of various cell death pathways (apoptosis/necrosis/autophagy) that synergistically modulate the neuronal death. Emerging evidence indicates that several proteins associated with early-onset familial PD play critical roles in mediating the neuronal death. Importantly, mutations in the genes encoding Parkin, PTEN-induced putative kinase 1 and DJ-1 mediate autosomal recessive forms of PD, whereas mutations in the genes encoding leucine-rich repeat kinase 2 and α-synuclein are responsible for autosomal dominant PD. This review discusses the significance of these proteins with the emphasis on the role of α-synuclein in mediating post-ischemic brain damage.

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Complex Network-Driven View of Genomic Mechanisms Underlying Parkinson’s Disease: Analyses in Dorsal Motor Vagal Nucleus, Locus Coeruleus, and Substantia Nigra

BioMed Research International ◽

10.1155/2014/543673 ◽

2014 ◽

Vol 2014 ◽

pp. 1-16 ◽

Cited By ~ 7

Author(s):

Beatriz Raposo Corradini ◽

Priscila Iamashita ◽

Edilaine Tampellini ◽

José Marcelo Farfel ◽

Lea Tenenholz Grinberg ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Locus Coeruleus ◽

Molecular Mechanisms ◽

Brain Regions ◽

Substantia Nigra Pars Compacta ◽

Gene Sets ◽

Coexpression Networks ◽

Ageing Brain

Parkinson’s disease (PD)—classically characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta—has a caudal-rostral progression, beginning in the dorsal motor vagal nucleus and, in a less extent, in the olfactory system, progressing to the midbrain and eventually to the basal forebrain and the neocortex. About 90% of the cases are idiopathic. To study the molecular mechanisms involved in idiopathic PD we conducted a comparative study of transcriptional interaction networks in the dorsal motor vagal nucleus (VA), locus coeruleus (LC), and substantia nigra (SN) of idiopathic PD in Braak stages 4-5 (PD) and disease-free controls (CT) using postmortem samples. Gene coexpression networks (GCNs) for each brain region (patients and controls) were obtained to identify highly connected relevant genes (hubs) and densely interconnected gene sets (modules). GCN analyses showed differences in topology and module composition between CT and PD networks for each anatomic region. In CT networks, VA, LC, and SN hub modules are predominantly associated with neuroprotection and homeostasis in the ageing brain, whereas in the patient’s group, for the three brain regions, hub modules are mostly related to stress response and neuron survival/degeneration mechanisms.

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The transcription factor BCL11A defines a distinctive subset of dopamine neurons in the developing and adult midbrain

10.1101/2020.10.06.327940 ◽

2020 ◽

Author(s):

Marianna Tolve ◽

Ayse Ulusoy ◽

Khondker Ushna Sameen Islam ◽

Gabriela O. Bodea ◽

Ece Öztürk ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Transcription Factor ◽

Substantia Nigra ◽

Motor Learning ◽

Molecular Mechanisms ◽

Dopaminergic System ◽

Dopamine Neurons ◽

Anatomical Changes ◽

Murine Brain

AbstractMidbrain dopaminergic (mDA) neurons are diverse in their projection targets, impact on behavior and susceptibility to neurodegeneration. Little is known about the molecular mechanisms that establish this diversity in mDA neurons during development. We find that the transcription factor Bcl11a defines a subset of mDA neurons in the developing and adult murine brain. By combining intersectional labeling and viral-mediated tracing we show that Bcl11a-expressing mDA neurons form a highly specific subcircuit within the dopaminergic system. We demonstrate that Bcl11a-expressing mDA neurons in the substantia nigra (SN) are particularly vulnerable to neurodegeneration in an α-synuclein overexpression model of Parkinson’s disease. Inactivation of Bcl11a in developing mDA neurons results in anatomical changes, deficits in motor learning and a dramatic increase in the susceptibility to α-synuclein-induced degeneration in SN-mDA neurons. In summary, we identify an mDA subpopulation with highly distinctive characteristics defined by the expression of the transcription factor Bcl11a already during development.

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Identification of Blood-based Biomarkers for Early Stage Parkinson’s Disease

10.1101/2020.10.22.20217893 ◽

2020 ◽

Author(s):

Andrew Gao

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Cellular Response ◽

Molecular Mechanisms ◽

Early Stage ◽

Differentially Expressed ◽

Motor Symptoms ◽

Early Stages

AbstractParkinson’s disease (PD) affects millions of people worldwide and causes symptoms such as bradykinesia and disrupted speech. Parkinson’s disease is known to be characterized by the mass death of dopaminergic neurons in the substantia nigra region. In the status quo, PD is often diagnosed at late stages because obvious motor symptoms appear after the disease has progressed far. It is advantageous to diagnose PD before the onset of motor symptoms because treatments are often more effective at early stages. While motor symptoms usually manifest when over 50% of dopaminergic neurons in the substantia nigra are already lost, molecular signatures of PD may be present at early stages in patient blood. This study aimed to analyze several gene expression studies’ data for commonly differentially expressed genes (DEGs) in the blood of early stage PD patients. 147 DEGs were identified in at least two out of three datasets and passed cut-off criteria. A protein interaction network for the DEGs was constructed and various tools were used to identify network characteristics and hub genes. PANTHER analysis revealed that the biological process “cellular response to glucagon stimulus” was overrepresented by almost 21 times among the DEGs and “lymphocyte differentiation” by 5.98 times. Protein catabolic processes and protein kinase functions were also overrepresented. ESR1, CD19, SMAD3, FOS, CXCR5, and PRKACA may be potential biomarkers and warrant further study. Overall, the findings of the present study provide insights on molecular mechanisms of PD and provide greater confidence on which genes are differentially expressed in PD. The results also are additional evidence for the role of the immune system in PD, a topic that is gaining interest in the PD research community.

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