Increased Striatal mRNA and Protein Levels of the Immunophilin FKBP-12 in Experimental Parkinson's Disease and Identification of FKBP-12-Binding Proteins

2007 ◽  
Vol 6 (10) ◽  
pp. 3952-3961 ◽  
Author(s):  
Anna Nilsson ◽  
Karl Sköld ◽  
Benita Sjögren ◽  
Marcus Svensson ◽  
Johan Pierson ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binding Proteins ◽  
Protein Levels

scholarly journals Fibroblasts from idiopathic Parkinson’s disease exhibit deficiency of lysosomal glucocerebrosidase activity associated with reduced levels of the trafficking receptor LIMP2

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ria Thomas ◽  
Elizabeth B. Moloney ◽  
Zachary K. Macbain ◽  
Penelope J. Hallett ◽  
Ole Isacson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Enzyme Activity ◽  
Current Data ◽  
Lysosomal Hydrolase ◽  
Protein Levels ◽  
Control Subjects ◽  
Er Retention ◽  
Trafficking Receptor ◽  
N370s Mutation

AbstractLysosomal dysfunction is a central pathway associated with Parkinson’s disease (PD) pathogenesis. Haploinsufficiency of the lysosomal hydrolase GBA (encoding glucocerebrosidase (GCase)) is one of the largest genetic risk factors for developing PD. Deficiencies in the activity of the GCase enzyme have been observed in human tissues from both genetic (harboring mutations in the GBA gene) and idiopathic forms of the disease. To understand the mechanisms behind the deficits of lysosomal GCase enzyme activity in idiopathic PD, this study utilized a large cohort of fibroblast cells from control subjects and PD patients with and without mutations in the GBA gene (N370S mutation) (control, n = 15; idiopathic PD, n = 31; PD with GBA N370S mutation, n = 6). The current data demonstrates that idiopathic PD fibroblasts devoid of any mutations in the GBA gene also exhibit reduction in lysosomal GCase activity, similar to those with the GBA N370S mutation. This reduced GCase enzyme activity in idiopathic PD cells was accompanied by decreased expression of the GBA trafficking receptor, LIMP2, and increased ER retention of the GBA protein in these cells. Importantly, in idiopathic PD fibroblasts LIMP2 protein levels correlated significantly with GCase activity, which was not the case in control subjects or in genetic PD GBA N370S cells. In conclusion, idiopathic PD fibroblasts have decreased GCase activity primarily driven by altered LIMP2-mediated transport of GBA to lysosome and the reduced GCase activity exhibited by  the genetic GBA N370S derived PD fibroblasts occurs through a different mechanism.

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 TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease

2017 ◽  
Vol 114 (40) ◽  
pp. 10773-10778 ◽  
Author(s):  
Seong Su Kang ◽  
Zhentao Zhang ◽  
Xia Liu ◽  
Fredric P. Manfredsson ◽  
Matthew J. Benskey ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Death ◽  
Kinase Domain ◽  
Alpha Synuclein ◽  
Mao B ◽  
Protein Levels ◽  
Trkb Receptors ◽  
Alpha Synuclein Aggregation ◽  
Neurotrophic Signaling

BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson’s disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase. Interestingly, α-Syn represses TrkB lipid raft distribution, decreases its internalization, and reduces its axonal trafficking. Moreover, α-Syn also reduces TrkB protein levels via up-regulation of TrkB ubiquitination. Remarkably, dopamine’s metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL) stimulates the interaction between α-Syn and TrkB. Accordingly, MAO-B inhibitor rasagiline disrupts α-Syn/TrkB complex and rescues TrkB neurotrophic signaling, preventing α-Syn–induced dopaminergic neuronal death and restoring motor functions. Hence, our findings demonstrate a noble pathological role of α-Syn in antagonizing neurotrophic signaling, providing a molecular mechanism that accounts for its neurotoxicity in PD.

scholarly journals Inhibition of FK506 Binding Proteins Reduces  -Synuclein Aggregation and Parkinson's Disease-Like Pathology

2010 ◽  
Vol 30 (7) ◽  
pp. 2454-2463 ◽  
Author(s):  
M. Gerard ◽  
A. Deleersnijder ◽  
V. Daniels ◽  
S. Schreurs ◽  
S. Munck ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binding Proteins ◽  
Fk506 Binding Proteins

scholarly journals A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

2021 ◽  
Vol 22 (7) ◽  
pp. 3708
Author(s):  
Jun Ogata ◽  
Kentaro Hirao ◽  
Kenya Nishioka ◽  
Arisa Hayashida ◽  
Yuanzhe Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Peripheral Blood ◽  
Kinase Activity ◽  
Late Onset ◽  
Causative Gene ◽  
Protein Levels ◽  
Wd40 Domain ◽  
Lrrk2 Protein ◽  
Familial Parkinson’S Disease

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.

Early ghrelin intervention protects against the progressive dopaminergic neuron loss in Parkinson’s disease mice

2020 ◽  
Author(s):  
Lingling Jiao ◽  
Fengju Jia ◽  
Xixun Du ◽  
Pei Zhang ◽  
Yong Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Weight Loss ◽  
Parkinson's Disease ◽  
Inflammatory Cytokine ◽  
Protective Factor ◽  
Subcutaneous Administration ◽  
Protein Levels ◽  
Potential Applications ◽  
Anti Oxidant ◽  
Anti Inflammatory

Abstract BackgroundGhrelin has been identified as a multifunctional peptide that has many potential applications for the treatment of various diseases, including Parkinson’s disease (PD). However, little is known about the pathophysiological function and mechanism of ghrelin in PD. MethodELISA was used for detecting plasma total and active ghrelin levels, dopamine (DA) content was measured by HPLC-ECD, immunofluorescence staining and Western blot were used to detect protein expressions, and cytokine was tested by Bio-PlexPro™ assay.ResultsHere, we reported a PD model that overexpressing mutant human A53T α-syn mice exhibited a decreased levels of total and active ghrelin in plasma, fewer tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN), lower DA content in the striatum (Str), and less weight. These changes were rescued by the subcutaneous administration of low-dose ghrelin. Interestingly, ghrelin had no effect on weight gain in wild-type mice but improved weight loss in A53T mice. In addition, ghrelin administration also attenuated the decreased Bcl-2/Bax ratio and superoxide dismutase1 (SOD1) protein levels and inhibited the upregulation pro-inflammatory cytokine interleukin-6 (IL-6) and tumour necrosis factor a (TNFa) and the downregulation of anti-inflammatory cytokine IL-10. In addition, ghrelin inhibited the increase in Iba1-positive cells in mice with PD.ConclusionsHere we reported that ghrelin had a protective effect on dopaminergic neurons and against weight loss from PD via anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms, which suggested that ghrelin could be an endogenous protective factor that prevents the onset or the progression of PD.

Protective effect of hydralazine on a cellular model of Parkinson’s disease: a possible role of hypoxia-inducible factor (HIF)-1α

2020 ◽  
Vol 98 (3) ◽  
pp. 405-414 ◽  
Author(s):  
Mehrnaz Mehrabani ◽  
Mohammad Hadi Nematollahi ◽  
Mojde Esmaeili Tarzi ◽  
Kobra Bahrampour Juybari ◽  
Moslem Abolhassani ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Antioxidant Power ◽  
Expression Levels ◽  
Downstream Target ◽  
Protein Levels ◽  
Ferric Reducing Antioxidant Power ◽  
6 Hydroxydopamine

Parkinson’s disease (PD) is a neurodegenerative disease accompanied by a low expression level of cerebral hypoxia-inducible factor (HIF-1α). Hence, activating the hypoxia-signaling pathway may be a favorable therapeutic approach for curing PD. This study explored the efficacy of hydralazine, a well-known antihypertensive agent, for restoring the impaired HIF-1 signaling in PD, with the aid of 6-hydroxydopamine (6-OHDA)-exposed SH-SY5Y cells. The cytotoxicity of hydralazine and 6-OHDA on the SH-SY5Y cells were evaluated by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and apoptosis detection assays. The activities of malondialdehyde, nitric oxide (NO), ferric reducing antioxidant power (FRAP), and superoxide dismutase (SOD) were also measured. Expression levels of HIF-1α and its downstream genes at the protein level were assessed by Western blotting. Hydralazine showed no toxic effects on SH-SY5Y cells, at the concentration of ≤50 μmol/L. Hydralazine decreased the levels of apoptosis, malondialdehyde, and NO, and increased the activities of FRAP and SOD in cells exposed to 6-OHDA. Furthermore, hydralazine up-regulated the protein expression levels of HIF-1α, vascular endothelial growth factor, tyrosine hydroxylase, and dopamine transporter in the cells also exposed to 6-OHDA, by comparison with the cells exposed to 6-OHDA alone. In summary, hydralazine priming could attenuate the deleterious effects of 6-OHDA on SH-SY5Y cells by increasing cellular antioxidant capacity, as well as the protein levels of HIF-1α and its downstream target genes.

scholarly journals Increased DJ-1 in Urine Exosome of Korean Males with Parkinson’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Dong Hwan Ho ◽  
Sanghak Yi ◽  
Hyemyung Seo ◽  
Ilhong Son ◽  
Wongi Seol
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dependent Manner ◽  
Protein Levels ◽  
Significant Difference ◽  
Daily Dose ◽  
Male Patients ◽  
And Gender ◽  
Urine Exosomes ◽  
Potential Use

Parkinson’s disease (PD) is a difficult disease to diagnose although it is the second most common neurodegenerative disease. Recent studies show that exosome isolated from urine contains LRRK2 or DJ-1, proteins whose mutations cause PD. To investigate a potential use for urine exosomes as a tool for PD diagnosis, we compared levels of LRRK2,α-synuclein, and DJ-1 in urine exosomes isolated from Korean PD patients and non-PD controls. LRRK2 and DJ-1, but notα-synuclein, were detected in the urine exosome samples, as reported previously. We initially could not detect any significant difference in these protein levels between the patient and the control groups. However, when age, disease duration, L-dopa daily dose, and gender were considered as analytical parameters, LRRK2 and DJ-1 protein levels showed clear gender-dependent differences. In addition, DJ-1 level was significantly higher (1.7-fold) in male patients with PD than that in male non-PD controls and increased in an age-dependent manner in male patients with PD. Our observation might provide a clue to lead to a novel biomarker for PD diagnosis, at least in males.

The effect of preventive exercise on the neuroprotection in 6-hydroxydopamine-lesioned rat brain

2019 ◽  
Vol 44 (12) ◽  
pp. 1267-1275 ◽  
Author(s):  
Zeinab Rezaee ◽  
Sayed Mohammad Marandi ◽  
Hojjatallah Alaei ◽  
Fahimeh Esfarjani
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Treadmill Running ◽  
Spatial Learning And Memory ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
6 Hydroxydopamine

Parkinson’s disease is characterized by neurodegeneration and learning deficiency. Physical exercise can alleviate these symptoms by increasing the expression of some effective and relevant factors. The preventive effect of 16-week treadmill running in a rat model of Parkinson’s disease, before 6-hydroxydopamine (6-OHDA) induction, was assessed. Experimental groups consisted of sedentary (SED), SED+6-OHDA, exercised (EX), and EX+6-OHDA rats. Forty-eight hours after the last session of exercise, 6-OHDA was injected into the medial forebrain bundle (MFB). One week after the injection, behavioral tests, including spatial learning and memory, were assessed through Morris water maze (MWM) and apomorphine-induced rotation. Three weeks after the injection, mRNA expression and protein levels of the transcriptional co-activator peroxisome-proliferator-activated receptor-γ co-activator-1α (PGC-1α), fibronectin type III domain-containing protein 5 (FNDC5), brain-derived neurotrophic factor (BDNF), and tyrosine hydroxylase (TH) were measured in the striatum and the hippocampus of rats by applying real-time PCR and Western blotting. The findings indicate that exposure to 6-OHDA leads to impairments in behavioral and molecular functions. Exercise training prevents and reduces the symptoms caused by dopamine toxins. The results suggest that treadmill running can exert neuroprotective and have preventive effects to reduce Parkinson’s disease symptoms. Novelty Parkinson’s disease impairs spatial learning and memory. Parkinson’s disease reduced levels of PGC-1α, FNDC5, and BDNF and increased neurodegeneration in the striatum and the hippocampus. Treadmill running before disease attenuated 6-OHDA-induced memory deficit and elevated neuroprotection. Exercise has multiple effects on memory and biochemical factors.

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.

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