Relationship S100 protein levels in blood plasma with a frequency of occurrence of cardiovascular complications in Parkinson's disease

The aim of the study is to investigate activity of markers of oxidative and nitrosative stresses in blood plasma of patients in the I–II stages of Parkinson’s disease (PD) and to determine correlations between their concentrations and severity of non-motor PD symptoms. Materials and methods. 67 patients at I–II PD stages and 20 healthy controls took part in the research. Cognitive functions were examined due to the Montreal Cognitive Assessment test – MoCA test. For the severity of psycho-emotional disorders evaluation the following scales and questionnaires were used: Night Sleep Assessment Questionnaire by A. M. Vein, Zung test for anxiety, apathy Starkstein scale, Boston stress-resistance test, Beck Depression Inventory (BDI-II). We performed ELISA test for determination of glutathione peroxidase (GPx) and glutathione-S-transferase (GST) activities and 3-nitrotyrosine (3-NT) level in blood plasma of participants (Elabscience® kit). Results. The middle age of PD patients and healthy controls was 64.35 ± 1.22 and 66.40 ± 0.70 years, respectively. GPx activity in plasma of patients at І–ІІ PD stages was significantly lower than in healthy controls (P < 0.001) and was higher at the I stage compared to the II PD stage (P = 0.003). Also GPx activity in PD patients with normal cognition was higher than in PD patients with cognitive impairment (P = 0.042). The GST activity in plasma of PD patients with anxiety was significantly lower (P = 0.002) compared to those without anxiety, and 3-NT blood plasma level in PD patients with moderate anxiety was higher than in those without one (P = 0.029). Conclusions. The activity of antioxidant GPx was significantly lower in PD patients at early stages compared to healthy controls, and in PD patients in the II stage of the disease compared to the I stage, and it was significantly lower in PD patients with cognitive impairment. PD patients with moderate anxiety had lower 3-NT levels and GST activity in blood plasma.

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

Molecular Brain ◽

10.1186/s13041-020-00712-3 ◽

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.

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Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

ASN NEURO ◽

10.1177/17590914211009730 ◽

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.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1713969114 ◽

2017 ◽

Vol 114 (40) ◽

pp. 10773-10778 ◽

Cited By ~ 40

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.

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

Journal of Proteome Research ◽

10.1021/pr070189e ◽

2007 ◽

Vol 6 (10) ◽

pp. 3952-3961 ◽

Cited By ~ 24

Author(s):

Anna Nilsson ◽

Karl Sköld ◽

Benita Sjögren ◽

Marcus Svensson ◽

Johan Pierson ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Binding Proteins ◽

Protein Levels

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

International Journal of Molecular Sciences ◽

10.3390/ijms22073708 ◽

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.

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