scholarly journals Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110097
Author(s):  
Kui Cui ◽  
Fan Yang ◽  
Turan Tufan ◽  
Muhammad U. Raza ◽  
Yanqiang Zhan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcription Factors ◽  
Disease Model ◽  
Neuronal Loss ◽  
Mrna Levels ◽  
Gene Therapies ◽  
Protein Levels ◽  
Dopaminergic Systems ◽  
And Function

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.

scholarly journals Graphene Oxide and Reduced Derivatives, as Powder or Film Scaffolds, Differentially Promote Dopaminergic Neuron Differentiation and Survival

2020 ◽  
Vol 14 ◽  
Author(s):  
Noela Rodriguez-Losada ◽  
Rune Wendelbob ◽  
M. Carmen Ocaña ◽  
Amelia Diaz Casares ◽  
Roberto Guzman de Villoría ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Graphene Oxide ◽  
Carbon Nanomaterials ◽  
Cell Loss ◽  
Synaptic Proteins ◽  
New Drugs ◽  
Neural Regeneration ◽  
Protein Levels ◽  
And Function

Emerging scaffold structures made of carbon nanomaterials, such as graphene oxide (GO) have shown efficient bioconjugation with common biomolecules. Previous studies described that GO promotes the differentiation of neural stem cells and may be useful for neural regeneration. In this study, we examined the capacity of GO, full reduced (FRGO), and partially reduced (PRGO) powder and film to support survival, proliferation, differentiation, maturation, and bioenergetic function of a dopaminergic (DA) cell line derived from the mouse substantia nigra (SN4741). Our results show that the morphology of the film and the species of graphene (GO, PRGO, or FRGO) influences the behavior and function of these neurons. In general, we found better biocompatibility of the film species than that of the powder. Analysis of cell viability and cytotoxicity showed good cell survival, a lack of cell death in all GO forms and its derivatives, a decreased proliferation, and increased differentiation over time. Neuronal maturation of SN4741 in all GO forms, and its derivatives were assessed by increased protein levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), the glutamate inward rectifying potassium channel 2 (GIRK2), and of synaptic proteins, such as synaptobrevin and synaptophysin. Notably, PRGO-film increased the levels of Tuj1 and the expression of transcription factors specific for midbrain DA neurons, such as Pitx3, Lmx1a, and Lmx1b. Bioenergetics and mitochondrial dysfunction were evaluated by measuring oxygen consumption modified by distinct GO species and were different between powder and film for the same GO species. Our results indicate that PRGO-film was the best GO species at maintaining mitochondrial function compared to control. Finally, different GO forms, and particularly PRGO-film was also found to prevent the loss of DA cells and the decrease of the α-synuclein (α-syn) in a molecular environment where oxidative stress has been induced to model Parkinson's disease. In conclusion, PRGO-film is the most efficient graphene species at promoting DA differentiation and preventing DA cell loss, thus becoming a suitable scaffold to test new drugs or develop constructs for Parkinson's disease cell replacement therapy.

scholarly journals Altered transcriptome-proteome coupling indicates aberrant proteostasis in Parkinson’s disease

2021 ◽  
Author(s):  
Fiona Dick ◽  
Ole-Bjørn Tysnes ◽  
Guido Werner Alves ◽  
Gonzalo S. Nido ◽  
Charalampos Tzoulis
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Level ◽  
Spatial Separation ◽  
Healthy Ageing ◽  
Mrna Levels ◽  
Protein Levels ◽  
A Genome ◽  
Genes Encoding ◽  
Ageing Brain

AbstractThe correlation between mRNA and protein levels has been shown to decline in the ageing brain, possibly reflecting age-dependent changes in the proteostasis. It is thought that impaired proteostasis may be implicated in the pathogenesis of Parkinson’s disease (PD), but evidence derived from the patient brain is currently limited. Here, we hypothesized that if impaired proteostasis occurs in PD, this should be reflected in the form of altered correlation between transcriptome and proteome compared to healthy ageing.To test this hypothesis, we integrated transcriptomic data with proteomics from prefrontal cortex tissue of 17 PD patients and 11 demographically matched healthy controls and assessed gene-specific correlations between RNA and protein level. To control for the effects of ageing, brain samples from 4 infants were included in the analyses.In the healthy aged brain, we observed a genome-wide decreased correlation between mRNA and protein levels. Moreover, a group of genes encoding synaptic vesicle proteins exhibited inverse correlations. This phenomenon likely reflects the spatial separation of mRNA and protein into the neuronal soma and synapsis, respectively, commonly characterizing these genes. Most genes showed a significantly lower correlation between mRNA and protein levels in PD compared to neurologically healthy ageing, consistent with a proteome-wide decline in proteostasis. Genes showing an inverse correlation in PD were enriched for proteasome subunits, suggesting that these proteins show accentuated spatial separation of transcript and protein between the soma and axon/synapses in PD neurons. Moreover, the PD brain was characterized by increased positive mRNA-protein correlation for some genes encoding components of the mitochondrial respiratory chain, suggesting these may require tighter regulation in the face of mitochondrial pathology characterizing the PD brain.Our results are highly consistent with a proteome-wide impairment of proteostasis in the PD brain and strongly support the hypothesis that aberrant proteasomal function is implicated in the pathogenesis of PD. Moreover, our findings have important implications for the correct interpretation of differential gene expression studies in PD. In the presence of disease-specific altered coupling of transcriptome and proteome, measured differences in mRNA levels cannot be used to infer changes at the protein-level and should be supplemented with direct determination of proteins nominated by the analyses.

scholarly journals Alterations of p11 in brain tissue and peripheral blood leukocytes in Parkinson’s disease

2017 ◽  
Vol 114 (10) ◽  
pp. 2735-2740 ◽  
Author(s):  
Holly Green ◽  
Xiaoqun Zhang ◽  
Katarina Tiklova ◽  
Nikolaos Volakakis ◽  
Lovisa Brodin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Nk Cell ◽  
The Body ◽  
Postmortem Brain ◽  
Cytotoxic T Cell ◽  
Mrna Levels ◽  
Comorbid Depression ◽  
Protein Levels

Individuals with Parkinson’s disease (PD) often suffer from comorbid depression. P11 (S100A10), a member of the S100 family of proteins, is expressed widely throughout the body and is involved in major depressive disorder and antidepressant response. Central p11 levels are reduced in postmortem tissue from depressed individuals; however, p11 has not yet been investigated in PD patients with depression or those without depression. We investigated p11 levels in postmortem PD brains and assessed whether peripheral p11 levels correlate with disease severity. Substantia nigra, putamen, and cortical p11 protein levels were assessed in postmortem brain samples from PD patients and matched controls. In a different set of postmortem brains, p11 mRNA expression was measured in dopaminergic cells from the substantia nigra. Both p11 protein and mRNA levels were decreased in PD patients. Peripheral p11 protein levels were investigated in distinct leukocyte populations from PD patients with depression and those without depression. Monocyte, natural killer (NK) cell, and cytotoxic T-cell p11 levels were positively associated with the severity of PD, and NK cell p11 levels were positively associated with depression scores. Given that inflammation plays a role in both PD and depression, it is intriguing that peripheral p11 levels are altered in immune cells in both conditions. Our data provide insight into the pathological alterations occurring centrally and peripherally in PD. Moreover, if replicated in other cohorts, p11 could be an easily accessible biomarker for monitoring the severity of PD, especially in the context of comorbid depression.

scholarly journals Laser Acupuncture at HT7 Acupoint Improves Cognitive Deficit, Neuronal Loss, Oxidative Stress, and Functions of Cholinergic and Dopaminergic Systems in Animal Model of Parkinson’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Jintanaporn Wattanathorn ◽  
Chatchada Sutalangka
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Cognitive Impairment ◽  
Stress Reduction ◽  
Memory Impairment ◽  
Neuronal Loss ◽  
Laser Acupuncture ◽  
Dopaminergic Systems

To date, the therapeutic strategy against cognitive impairment in Parkinson’s disease (PD) is still not in satisfaction level and requires novel effective intervention. Based the oxidative stress reduction and cognitive enhancement induced by laser acupuncture at HT7, the beneficial effect of laser acupuncture at HT7 against cognitive impairment in PD has been focused. In this study, we aimed to determine the effect of laser acupuncture at HT7 on memory impairment, oxidative stress status, and the functions of both cholinergic and dopaminergic systems in hippocampus of animal model of PD. Male Wistar rats, weighing 180–220 g, were induced unilateral lesion at right substantianigra by 6-OHDA and were treated with laser acupuncture continuously at a period of 14 days. The results showed that laser acupuncture at HT7 enhanced memory and neuron density in CA3 and dentate gyrus. The decreased AChE, MAO-B, and MDA together with increased GSH-Px in hippocampus of a 6-OHDA lesion rats were also observed. In conclusion, laser acupuncture at HT7 can improve neuron degeneration and memory impairment in animal model of PD partly via the decreased oxidative stress and the improved cholinergic and dopaminergic functions. More researches concerning effect of treatment duration are still required.

scholarly journals Expression of Transcription Factors in CD4 + T Cells as Potential Biomarkers of Motor Complications in Parkinson’s Disease

2020 ◽  
pp. 1-8
Author(s):  
Elena Contaldi ◽  
Luca Magistrelli ◽  
Anna Vera Milner ◽  
Marco Cosentino ◽  
Franca Marino ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
T Cells ◽  
Transcription Factors ◽  
Cd4 T Cells ◽  
Mrna Levels ◽  
Molecular Signatures ◽  
Motor Complications ◽  
Roc Curve Analysis ◽  
Long Term Treatment

Background: Management of motor complications (MC) represents a major challenge in the long-term treatment of Parkinson’s disease (PD) patients. In this context, the role of peripheral adaptive immunity may provide new insights, since neuroinflammatory mechanisms have been proved crucial in the disease. Objective: The aim of this study was to analyze the transcription factors genes involved in CD4 + T cells development to uncover specific molecular signatures in patients with (PMC) and without (WMC) motor complications. Methods: mRNA levels of CD4 + T lymphocytes transcription factor genes TBX21, STAT1, STAT3, STAT4, STAT6, RORC, GATA3, FOXP3, and NR4A2 were measured from 40 PD patients, divided into two groups according to motor complications. Also, 40 age- and sex-matched healthy controls were enrolled. Results: WMC patients had higher levels of STAT1 and NR4A2 (p = 0.004; p = 0.003), whereas in PMC we found higher levels of STAT6 (p = 0.04). Also, a ROC curve analysis confirmed STAT1 and NR4A2 as feasible biomarkers to discriminate WMC (AUC = 0.76, 95%CI 0.59–0.92, p = 0.005; AUC = 0.75, 95%CI 0.58–0.90, p = 0.007). Similarly, STAT6 detected PMC patients (AUC = 0.69, 95%CI 0.52–0.86, p = 0.037). Conclusion: These results provide evidence of different molecular signatures in CD 4 + T cells of PD patients with and without MC, thus suggesting their potential as biomarkers of MC development.

scholarly journals Grafts Derived from an α-Synuclein Triplication Patient Mediate Functional Recovery but Develop Disease-Associated Pathology in the 6-OHDA Model of Parkinson’s Disease

2020 ◽  
pp. 1-14
Author(s):  
Shelby Shrigley ◽  
Fredrik Nilsson ◽  
Bengt Mattsson ◽  
Alessandro Fiorenzano ◽  
Janitha Mudannayake ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Lines ◽  
Functional Recovery ◽  
Embryonic Stem ◽  
Hesc Line ◽  
Alternative Source ◽  
And Function

Background: Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson’s disease (PD) and they provide the option of using the patient’s own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD. Objective: To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α-synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line (RC17) as a reference control. Methods: Cells were differentiated into ventral mesencephalic (VM)-patterned DA progenitors using an established GMP protocol. The progenitors were then either terminally differentiated to mature DA neurons in vitro or transplanted into 6-hydroxydopamine (6-OHDA) lesioned rats and their survival, maturation, function, and propensity to develop α-synuclein related pathology, were assessed in vivo. Results: Both cell lines generated functional neurons with DA properties in vitro. AST18-derived VM progenitor cells survived transplantation and matured into neuron-rich grafts similar to the RC17 cells. After 24 weeks, both cell lines produced DA-rich grafts that mediated full functional recovery; however, pathological changes were only observed in grafts derived from the α-synuclein triplication patient line. Conclusion: This data shows proof-of-principle for survival and functional recovery with familial PD patient-derived cells in the 6-OHDA model of PD. However, signs of slowly developing pathology warrants further investigation before use of autologous grafts in patients.

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