Striatal glutamate induces retrograde excitotoxicity and neuronal degeneration of intralaminar thalamic nuclei: their potential relevance for Parkinson's disease

2013 ◽  
Vol 38 (1) ◽  
pp. 2172-2182 ◽  
Author(s):  
Ingrid Morales ◽  
Magdalena Sabate ◽  
Manuel Rodriguez
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Degeneration ◽  
Thalamic Nuclei ◽  
Intralaminar Thalamic Nuclei

110 Atrophy of the mediodorsal thalamus is associated with visual hallucinations in lewy body diseases

2018 ◽  
Vol 89 (6) ◽  
pp. A43.3-A44
Author(s):  
Elie Matar ◽  
Daniel Brooks ◽  
Antony Harding ◽  
Glenda Halliday
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Neuronal Degeneration ◽  
Neuronal Loss ◽  
Lewy Body Disease ◽  
Visual Hallucinations ◽  
Volume Loss ◽  
Thalamic Nuclei ◽  
Mediodorsal Thalamus

IntroductionAlthough limbic system dysfunction has been thought to underlie visual hallucinations in patients with Lewy body disorders, neuropathology within thalamic structures subserving limbic functions have not been examined. In this study, we assessed the degree of neuronal degeneration in thalamic regions involved in perceptual integration in patients with Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB).MethodsPost-mortem samples were acquired from twenty-four individuals with Lewy body disease (5 PD, 9 PDD, 10 DLB) and 10 age-matched controls. The anterior principal (AP) and mediodorsal (MD) thalamic nuclei were delineated and analysed using stereological and quantitative neuropathological techniques.ResultsVolume loss within the MD nucleus was observed in patients with DLB (31%) and PDD (18%) but not PD compared to controls (ANOVA, p<0.05). The atrophy was significantly greater in those patients with hallucinations than those without (p<0.05). Somal atrophy was seen in all patient groups and did not correlate with volume loss or visual hallucinations. Interestingly, there was no neuronal loss in this region compared to controls in the Lewy body disease groups. Analysis of the AP nucleus revealed similar patterns of volume loss but with somal atrophy only in patients with PDD and DLB. Both these measures did not correlate significantly with visual hallucinations, but was significantly different in patients with dementia compared to PD only and controls (p<0.05).ConclusionThese results suggest that afferent denervation of the mediodorsal thalamus may contribute to visual hallucinations. This appears to support models that implicate upstream components of the limbic circuitry in the generation of this phenomenon.

scholarly journals Neuronal loss in the caudal intralaminar thalamic nuclei in a primate model of Parkinson’s disease

2013 ◽  
Vol 219 (1) ◽  
pp. 381-394 ◽  
Author(s):  
R. M. Villalba ◽  
T. Wichmann ◽  
Y. Smith
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Loss ◽  
Thalamic Nuclei ◽  
Primate Model ◽  
Intralaminar Thalamic Nuclei

Impact of surgery targeting the caudal intralaminar thalamic nuclei on the pathophysiological functioning of basal ganglia in a rat model of Parkinson’s disease

2009 ◽  
Vol 78 (2-3) ◽  
pp. 80-84 ◽  
Author(s):  
Lydia Kerkerian-Le Goff ◽  
Jean-Jacques Bacci ◽  
Loreline Jouve ◽  
Christophe Melon ◽  
Pascal Salin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Rat Model ◽  
Thalamic Nuclei ◽  
Intralaminar Thalamic Nuclei

scholarly journals Changes in excitability properties of ventromedial motor thalamic neurons in 6-OHDA lesioned mice

2020 ◽  
Author(s):  
Edyta K Bichler ◽  
Francesco Cavarretta ◽  
Dieter Jaeger
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Potassium Current ◽  
Cellular Level ◽  
Inhibitory Input ◽  
Dopamine Depletion ◽  
Thalamic Nuclei ◽  
Adult Mice ◽  
Motor Thalamus

AbstractThe activity of basal ganglia input receiving motor thalamus (BGMT) makes a critical impact on motor cortical processing, but modification in BGMT processing with Parkinsonian conditions have not be investigated at the cellular level. Such changes may well be expected due to homeostatic regulation of neural excitability in the presence of altered synaptic drive with dopamine depletion. We addressed this question by comparing BGMT properties in brain slice recordings between control and unilaterally 6-OHDA treated adult mice. At a minimum of 1 month post 6-OHDA treatment, BGMT neurons showed a highly significant increase in intrinsic excitability, which was primarily due to a decrease in M-type potassium current. BGMT neurons after 6-OHDA treatment also showed an increase in T-type calcium rebound spikes following hyperpolarizing current steps. Biophysical computer modeling of a thalamic neuron demonstrated that an increase in rebound spiking can also be accounted for by a decrease in the M-type potassium current. Modeling also showed that an increase in sag with hyperpolarizing steps found after 6-OHDA treatment could in part but not fully be accounted for by the decrease in M-type current. These findings support the hypothesis that homeostatic changes in BGMT neural properties following 6-OHDA treatment likely influence the signal processing taking place in basal ganglia thalamocortical processing in Parkinson’s disease.Significance StatementOur investigation of the excitability properties of neurons in the basal ganglia input receiving motor thalamus (BGMT) is significant because they are likely to be different from properties in other thalamic nuclei due to the additional inhibitory input stream these neurons receive. Further, they are important to understand the role of BGMT in the dynamic dysfunction of cortico – basal ganglia circuits in Parkinson’s disease. We provide clear evidence that after 6-OHDA treatment of mice important homeostatic changes occur in the intrinsic properties of BGMT neurons. Specifically we identify the M-type potassium current as an important thalamic excitability regulator in the parkinsonian state.

scholarly journals Stem Cell Therapy: A Promising Treatment of Parkinson’s Diseases

2021 ◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Progression ◽  
Dopaminergic Neurons ◽  
Cellular Therapy ◽  
Neurodegenerative Disorder ◽  
Neuronal Degeneration ◽  
Cell Types ◽  
Parkinson’S Diseases ◽  
Multipotent Mesenchymal Stem Cells

The neurodegenerative disorder is a prolonged persistence curse and effect on economic and physical challenges in an aging world. Parkinson has come in the second category of disability disorders and associated with progressive dopaminergic neuronal degeneration with severe motor complications. It is an observation that gradual disease progression causes 70% degeneration of striatal dopaminergic neurons. Globally there are around 7-10 million patients with Parkinson's disease, however, there are huge efforts for therapeutic improvement. According to studies, no single molecular pathway was pointed out as a single etiology to control disease progression due to a lack of targeted therapeutic strategies. Previously implemented symptomatic treatments include L-dopa (L-3,4-dihydroxyphenylalanine), deep brain stimulation, and the surgical insertion of a medical device. This leads to dyskinesia, dystonia and a higher risk of major surgical complications respectively. However, not all the above-mentioned therapies cannot regenerate the dopaminergic neurons in Parkinson’s disease patients. Recent advances in the field of cellular therapy have shown promising outcomes by differentiation of multipotent mesenchymal stem cells into dopaminergic neurons under the influence of a regenerative substance. In this review, we have discussed the differentiation of dopaminergic neurons by using different cell types that can be used as a cellular therapeutic approach for Parkinson’s disease. The information was collected through a comprehensive search using the keywords, “Parkinson Disease, Dopamine, Brain derived neurotrophic factor and neuron from reliable search engines, PubMed, Google Scholar and Medline reviews from the year 2010 to 2020.

scholarly journals Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

2019 ◽  
Author(s):  
Minhong Huang ◽  
Dan Lou ◽  
Adhithiya Charli ◽  
Dehui Kong ◽  
Huajun Jin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Neuronal Degeneration ◽  
Ex Vivo ◽  
Genetic Mutation ◽  
Common Mechanism ◽  
Enhancer Activity ◽  
Active Enhancer ◽  
Environmental Component

AbstractGenetic mutations explain only 10-15% of cases of Parkinson’s disease (PD), while an overriding environmental component has been implicated in the etiopathogenesis of PD. But regardless of where the underlying triggers for the onset of familial and sporadic PD fall on the gene-environment axis, mitochondrial dysfunction emerges as a common mediator of dopaminergic neuronal degeneration. Herein, we employ a multidisciplinary approach to convincingly demonstrate that neurotoxicant exposure- and genetic mutation-driven mitochondrial dysfunction share a common mechanism of epigenetic dysregulation. Under both scenarios, lysine 27 acetylation of likely variant H3.2 (H3.2K27ac) increased in dopaminergic neuronal models of PD, thereby opening that region to active enhancer activity via H3K27 hyperacetylation. These vulnerable epigenomic loci represent potential transcription factor motifs for PD pathogenesis. We further confirmed the mitochondrial dysfunction induced H3K27ac during neurodegeneration in ex vivo models of PD. Our results reveal an exciting axis of ‘exposure/mutation-mitochondrial dysfunction-metabolism-H3K27ac-transcriptome’ for PD pathogenesis. Collectively, the novel mechanistic insights presented here interlinks mitochondrial dysfunction to epigenetic transcriptional regulation in dopaminergic degeneration as well as offer potential new epigenetic intervention strategies for PD.

Protective and therapeutic activity of honokiol in reversing motor deficits and neuronal degeneration in the mouse model of Parkinson’s disease

2018 ◽  
Vol 70 (4) ◽  
pp. 668-676 ◽  
Author(s):  
Hwei-Hsien Chen ◽  
Pei-Chi Chang ◽  
Chinpiao Chen ◽  
Ming-Huan Chan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Neuronal Degeneration ◽  
Motor Deficits ◽  
Therapeutic Activity

Identification of Molecular Mechanisms in Parkinson’s Disease Pathogenesis: Significance of Survival and Inflammation Pathways

2020 ◽  
Author(s):  
Zerrin Karaaslan ◽  
Ozlem Timirci Kahraman ◽  
Elif Sanli ◽  
Hayriye Arzu Ergen ◽  
Basar Bilgic ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Functional Annotation ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Neuronal Degeneration ◽  
Expression Profiles ◽  
Quantitative Polymerase Chain Reaction ◽  
Rt Pcr ◽  
Peripheral Blood Mononuclear

Abstract Background: Our aim was to identify the differentially expressed genes (DEGs) between Parkinson’s disease (PD) patients and controls by microarray technology and analysis of related molecular pathways by functional annotation. Methods: Thirty PD patients and 30 controls were enrolled. Agilent Human 8X60 K Oligo Microarray was used for gene level expression identification. Gene ontology and pathway enrichment analyses were used for functional annotation of DEGs. Protein-protein interaction analyses were performed with STRING. Expression levels of randomly selected 5 genes among DEGs were quantified by real time quantitative polymerase chain reaction (RT-PCR) for validation. Flow cytometry was done to determine frequency of regulatory T cells (Tregs) in peripheral blood mononuclear cells. Results: A total of 361 DEGs (143 upregulated and 218 downregulated) were identified after GeneSpring analysis. DEGs were involved in 28 biological processes, 12 cellular components and 26 molecular functions. Pathway analyses demonstrated that upregulated genes mainly enriched in p53 (CASP3, TSC2, ATR, MDM4, CCNG1) and PI3K/Akt (IL2RA, IL4R, TSC2, VEGFA, PKN2, PIK3CA, ITGA4, BCL2L11) signaling pathways. TP53 and PIK3CA were identified as most significant hub proteins. Expression profiles obtained by RT-PCR were consistent with microarray findings. PD patients showed increased proportions of CD49d+ Tregs, which correlated with disability scores. Discussion: Survival pathway genes were upregulated putatively to compensate neuronal degeneration. Bioinformatics analysis showed an association between survival and inflammation genes. Increased CD49d+ Treg ratios might signify the attempt of the immune system to suppress ongoing inflammation. Conclusion: Altered functions of Tregs might have an important role in PD pathogenesis and CD49d expression could be a prognostic biomarker of PD.

The role of α-synuclein in neurodegeneration — An update

2012 ◽  
Vol 3 (2) ◽  
Author(s):  
Kurt Jellinger
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Bound States ◽  
Physiological Function ◽  
Neuronal Degeneration ◽  
Association Studies ◽  
Common Mechanism ◽  
Genome Wide Association Studies ◽  
Potential Biomarker

AbstractGenetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson’s disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson’s disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

scholarly journals Molecular targets for endogenous glial cell line-derived neurotrophic factor modulation in striatal parvalbumin interneurons

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Daniel Enterría-Morales ◽  
Natalia López-González del Rey ◽  
Javier Blesa ◽  
Ivette López-López ◽  
Sarah Gallet ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Neuronal Degeneration ◽  
Molecular Targets ◽  
Membrane Receptors ◽  
Parvalbumin Interneurons ◽  
Parvalbumin Neurons

Abstract Administration of recombinant glial cell line-derived neurotrophic factor into the putamen has been tested in preclinical and clinical studies to evaluate its neuroprotective effects on the progressive dopaminergic neuronal degeneration that characterizes Parkinson’s disease. However, intracerebral glial cell line-derived neurotrophic factor infusion is a challenging therapeutic strategy, with numerous potential technical and medical limitations. Most of these limitations could be avoided if the production of endogenous glial cell line-derived neurotrophic factor could be increased. Glial cell line-derived neurotrophic factor is naturally produced in the striatum from where it exerts a trophic action on the nigrostriatal dopaminergic pathway. Most of striatal glial cell line-derived neurotrophic factor is synthesized by a subset of GABAergic interneurons characterized by the expression of parvalbumin. We sought to identify molecular targets specific to those neurons and which are putatively associated with glial cell line-derived neurotrophic factor synthesis. To this end, the transcriptomic differences between glial cell line-derived neurotrophic factor-positive parvalbumin neurons in the striatum and parvalbumin neurons located in the nearby cortex, which do not express glial cell line-derived neurotrophic factor, were analysed. Using mouse reporter models, we have defined the genomic signature of striatal parvalbumin interneurons obtained by fluorescence-activated cell sorting followed by microarray comparison. Short-listed genes were validated by additional histological and molecular analyses. These genes code for membrane receptors (Kit, Gpr83, Tacr1, Tacr3, Mc3r), cytosolic proteins (Pde3a, Crabp1, Rarres2, Moxd1) and a transcription factor (Lhx8). We also found the proto-oncogene cKit to be highly specific of parvalbumin interneurons in the non-human primate striatum, thus highlighting a conserved expression between species and suggesting that specific genes identified in mouse parvalbumin neurons could be putative targets in the human brain. Pharmacological stimulation of four G-protein-coupled receptors enriched in the striatal parvalbumin interneurons inhibited Gdnf expression presumably by decreasing cyclic adenosine monophosphate formation. Additional experiments with pharmacological modulators of adenylyl cyclase and protein kinase A indicated that this pathway is a relevant intracellular route to induce Gdnf gene activation. This preclinical study is an important step in the ongoing development of a specific pro-endo-glial cell line-derived neurotrophic factor pharmacological strategy to treat Parkinson’s disease.

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