scholarly journals The proSAAS chaperone provides neuroprotection and attenuates transsynaptic α–synuclein spread in rodent models of Parkinson’s disease

2021 ◽  
Author(s):  
Iris Lindberg ◽  
Zhan Shu ◽  
Hoa Lam ◽  
Michael Helwig ◽  
Nur Yucer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Tyrosine Hydroxylase ◽  
Motor Function ◽  
Motor Disorder ◽  
Chaperone Protein ◽  
Significant Amelioration ◽  
Therapeutic Development ◽  
Neuroprotective Function

ABSTRACTParkinson’s disease is a devastating motor disorder involving the aberrant aggregation of the synaptic protein synuclein (aSyn) and degeneration of the nigrostriatal dopaminergic tract. We previously showed that proSAAS, a small secreted chaperone protein widely expressed in neurons within the brain, is able to block aSyn-induced dopaminergic cytotoxicity in primary nigral neuron cultures. We show here that coinjection of proSAAS-encoding lentivirus profoundly reduced the motor asymmetry caused by unilateral nigral AAV-mediated human aSyn overexpression. This positive functional outcome was accompanied by significant amelioration of the human aSyn-induced loss of both nigral tyrosine hydroxylase-positive cells and striatal tyrosine hydroxylase-positive terminals, demonstrating clear proSAAS-mediated protection of the nigro-striatal tract. ProSAAS overexpression also reduced the content of human aSyn protein in both the nigra and striatum and reduced the loss of tyrosine hydroxylase protein in both regions. Since proSAAS is a secreted protein, we tested the possibility that proSAAS is able to block the transsynaptic spread of aSyn from the periphery to the central nervous system, increasingly recognized as a potentially significant pathological mechanism. The number of human aSyn-positive neurites in the pons and caudal midbrain of mice following administration of human aSyn-encoding AAV into the vagus nerve was considerably reduced in mice coinjected with proSAAS-encoding AAV, supporting proSAAS-mediated blockade of transsynaptic aSyn transmission. We suggest that proSAAS may represent a promising target for therapeutic development in Parkinson’s disease.SignificanceThis paper describes two independent avenues of research that both provide support for the in vivo neuroprotective function of this small chaperone protein. In the first approach, we show that proSAAS overexpression provides remarkably effective protection against dopaminergic neurotoxicity in a rat model of Parkinson’s disease. This conclusion is supported both by three independent assays of motor function as well as by quantitative analysis of surviving dopaminergic neurons in brain areas involved in the control of motor function. In the second line of research, we show that in mice, the spread of human synuclein across synapses can be blunted by proSAAS overexpression.

scholarly journals Nervonic acid amends motor disorder in a mouse model of Parkinson’s disease

2021 ◽  
Vol 12 (1) ◽  
pp. 237-246
Author(s):  
Dandong Hu ◽  
Yujuan Cui ◽  
Ji Zhang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Tyrosine Hydroxylase ◽  
Mouse Model ◽  
Nervonic Acid ◽  
Motor Disorder ◽  
Behavioral Deficits ◽  
Liver And Kidney ◽  
The Impact

Abstract Objectives Parkinson’s disease (PD) is a kind of common neurodegenerative disease in the world. Previous studies have proved that nervonic acid (NA), extracted from Xanthoceras sorbifolia Bunge, has the potentials of neuroprotection. However, the effect of NA on the PD remained unknown. This study was designed to investigate the NA’s potential function and relative mechanism on motor disorder. Methods 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used for producing parkinsonism motor disorder on male C57BL/6 mice. Toxicity experiments and behavioral assay were performed to evaluate the effect of NA. Besides, the expression levels of tyrosine hydroxylase and α-synuclein, as well as striatal dopamine (DA), serotonin, and their metabolites were explored through immunoblotting and chromatography after NA treatment in vivo. Results We found that NA could alleviate the MPTP-induced behavioral deficits dose-dependently. Moreover, NA has no toxic effects on the mouse liver and kidney. Of note, we found that NA significantly reduced the impact of MPTP impairment and striatal DA, serotonin, and metabolites were remained unaffected. In addition, tyrosine hydroxylase was upregulated while α-synuclein being downregulated and the oxidative stress was partially repressed evidenced by the upregulation of superoxide dismutase and glutathione activity after NA treatment. Conclusion Our findings unveil NA’s potential for protecting motor system against motor disorder in the PD mouse model without any side effects, indicating NA as an alternative strategy for PD symptom remission.

scholarly journals Increased Activity of Tyrosine Hydroxylase Leads to Elevated Amphetamine Response and Markers of Oxidative Stress in Transgenic Mice

2017 ◽  
Author(s):  
Laura M. Vecchio ◽  
M. Kristel Bermejo ◽  
Amy Dunn ◽  
Marija Milenkovic ◽  
Nikhil Urs ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Tyrosine Hydroxylase ◽  
Dopamine Synthesis ◽  
Dopamine Turnover ◽  
Nigrostriatal Pathway ◽  
Adult Mice

AbstractIn Parkinson’s disease, noradrenergic cells of the locus coeruleus and dopamine cells within the nigrostriatal pathway undergo profound degeneration. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the production of all catecholamines, including dopamine and noradrenaline, and is selectively expressed in the cells that produce these neurotransmitters. In vitro studies have previously shown that the TH-synthetic system can contribute to the formation of reactive oxygen species. In addition, animal models of dopamine mishandling demonstrated that free dopamine is neurotoxic. To examine how increased TH activity might influence catecholamine systems in vivo, we generated TH-overexpressing mice (TH-HI) with six total copies of the TH murine gene. A commensurate increase in TH mRNA produced a threefold increase in both total TH protein and phosphorylated TH levels. We found an increased rate of dopamine synthesis in both young and adult mice, reflected by the accumulation of L-DOPA following NSD-1015 administration, as well as elevated dopamine tissue content in young mice and an increased presence of dopamine metabolites at both ages. Adult mice show no difference in baseline locomotor behaviour compared to wildtype littermates, but a have potentiated response to amphetamine. In addition to elevated dopamine turnover in the striatum, TH-HI mice show reduced levels of glutathione and increased levels of cysteinylated catechols. These results indicate that a heightened level of active TH can produce oxidative stress, and may represent a source of toxicity that is specific to catecholamine cells, which are most vulnerable to degeneration in Parkinson’s disease.

In vivo multimodal (MRI, SPECT) imaging of the 6-OHDA rat model for Parkinson's disease correlated with behavior and histology

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S392-S392
Author(s):  
Nadja Van Camp ◽  
Koen Van Laere ◽  
Ruth Vreys ◽  
Marleen Verhoye ◽  
Erwin Lauwers ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Spect Imaging ◽  
Multimodal Mri

Pharmacological treatment with L-DOPA may reduce striatal dopamine transporter binding in in vivo imaging studies

2016 ◽  
Vol 55 (01) ◽  
pp. 21-28 ◽  
Author(s):  
C. Antke ◽  
H. Hautzel ◽  
H.-W. Mueller ◽  
S. Nikolaus
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binding Sites ◽  
Human Subjects ◽  
Synaptic Cleft ◽  
Presynaptic Terminal ◽  
Imaging Studies ◽  
Psychiatric Conditions ◽  
Da Release

SummaryNumerous neurologic and psychiatric conditions are treated with pharmacological compounds, which lead to an increase of synaptic dopamine (DA) levels. One example is the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted to DA in the presynaptic terminal. If the increase of DA concentrations in the synaptic cleft leads to competition with exogenous radioligands for presynaptic binding sites, this may have implications for DA transporter (DAT) imaging studies in patients under DAergic medication.This paper gives an overview on those findings, which, so far, have been obtained on DAT binding in human Parkinson’s disease after treatment with L-DOPA. Findings, moreover, are related to results obtained on rats, mice or non-human primates. Results indicate that DAT imaging may be reduced in the striata of healthy animals, in the unlesioned striata of animal models of unilateral Parkinson’s disease and in less severly impaired striata of Parkinsonian patients, if animal or human subjects are under acute or subchronic treatment with L-DOPA. If also striatal DAT binding is susceptible to alterations of synaptic DA levels, this may allow to quantify DA reuptake in analogy to DA release by assessing the competition between endogenous DA and the administered exogenous DAT radioligand.

Effects of music-based movement therapy on motor function, balance, gait, mental health, and quality of life for patients with Parkinson’s disease: A systematic review and meta-analysis

2021 ◽  
pp. 026921552199052
Author(s):  
Zonglei Zhou ◽  
Ruzhen Zhou ◽  
Wen Wei ◽  
Rongsheng Luan ◽  
Kunpeng Li
Keyword(s):  
Quality Of Life ◽  
Mental Health ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Motor Function ◽  
Meta Analysis ◽  
Freezing Of Gait ◽  
Movement Therapy ◽  
Walking Velocity

Objective: To conduct a systematic review evaluating the effects of music-based movement therapy on motor function, balance, gait, mental health, and quality of life among individuals with Parkinson’s disease. Data sources: A systematic search of PubMed, Embase, Cochrane Library, Web of Science, PsycINFO, CINAHL, and Physiotherapy Evidence Database was carried out to identify eligible papers published up to December 10, 2020. Review methods: Literature selection, data extraction, and methodological quality assessment were independently performed by two investigators. Publication bias was determined by funnel plot and Egger’s regression test. “Trim and fill” analysis was performed to adjust any potential publication bias. Results: Seventeen studies involving 598 participants were included in this meta-analysis. Music-based movement therapy significantly improved motor function (Unified Parkinson’s Disease Rating Scale motor subscale, MD = −5.44, P = 0.002; Timed Up and Go Test, MD = −1.02, P = 0.001), balance (Berg Balance Scale, MD = 2.02, P < 0.001; Mini-Balance Evaluation Systems Test, MD = 2.95, P = 0.001), freezing of gait (MD = −2.35, P = 0.039), walking velocity (MD = 0.18, P < 0.001), and mental health (SMD = −0.38, P = 0.003). However, no significant effects were observed on gait cadence, stride length, and quality of life. Conclusion: The findings of this study show that music-based movement therapy is an effective treatment approach for improving motor function, balance, freezing of gait, walking velocity, and mental health for patients with Parkinson’s disease.

scholarly journals Growth Factor Therapy for Parkinson’s Disease: Alternative Delivery Systems

2021 ◽  
pp. 1-7
Author(s):  
Sarah Jarrin ◽  
Abrar Hakami ◽  
Ben Newland ◽  
Eilís Dowd
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Growth Factors ◽  
Growth Factor ◽  
Ex Vivo ◽  
Brain Regions ◽  
Delivery Systems ◽  
Alternative Delivery

Despite decades of research and billions in global investment, there remains no preventative or curative treatment for any neurodegenerative condition, including Parkinson’s disease (PD). Arguably, the most promising approach for neuroprotection and neurorestoration in PD is using growth factors which can promote the growth and survival of degenerating neurons. However, although neurotrophin therapy may seem like the ideal approach for neurodegenerative disease, the use of growth factors as drugs presents major challenges because of their protein structure which creates serious hurdles related to accessing the brain and specific targeting of affected brain regions. To address these challenges, several different delivery systems have been developed, and two major approaches—direct infusion of the growth factor protein into the target brain region and in vivo gene therapy—have progressed to clinical trials in patients with PD. In addition to these clinically evaluated approaches, a range of other delivery methods are in various degrees of development, each with their own unique potential. This review will give a short overview of some of these alternative delivery systems, with a focus on ex vivo gene therapy and biomaterial-aided protein and gene delivery, and will provide some perspectives on their potential for clinical development and translation.

scholarly journals Effectiveness and mechanisms of adipose-derived stem cell therapy in animal models of Parkinson’s disease: a systematic review and meta-analysis

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Keya Li ◽  
Xinyue Li ◽  
Guiying Shi ◽  
Xuepei Lei ◽  
Yiying Huang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Therapeutic Option ◽  
Meta Analysis ◽  
Future Application ◽  
Neuroprotective Effects ◽  
Standard Mean Difference ◽  
Study Characteristics

AbstractAnimal models provide an opportunity to assess the optimal treatment way and the underlying mechanisms of direct clinical application of adipose-derived stem cells (ADSCs). Previous studies have evaluated the effects of primitive and induced ADSCs in animal models of Parkinson’s disease (PD). Here, eight databases were systematically searched for studies on the effects and in vivo changes caused by ADSC intervention. Quality assessment was conducted using a 10-item risk of bias tool. For the subsequent meta-analysis, study characteristics were extracted and effect sizes were computed. Ten out of 2324 published articles (n = 169 animals) were selected for further meta-analysis. After ADSC therapy, the rotation behavior (10 experiments, n = 156 animals) and rotarod performance (3 experiments, n = 54 animals) were improved (P < 0.000 01 and P = 0.000 3, respectively). The rotation behavior test reflected functional recovery, which may be due to the neurogenesis from neuronally differentiated ADSCs, resulting in a higher pooled effect size of standard mean difference (SMD) (− 2.59; 95% CI, − 3.57 to − 1.61) when compared to that of primitive cells (− 2.18; 95% CI, − 3.29 to − 1.07). Stratified analyses by different time intervals indicated that ADSC intervention exhibited a long-term effect. Following the transplantation of ADSCs, tyrosine hydroxylase-positive neurons recovered in the lesion area with pooled SMD of 13.36 [6.85, 19.86]. Transplantation of ADSCs is a therapeutic option that shows long-lasting effects in animal models of PD. The potential mechanisms of ADSCs involve neurogenesis and neuroprotective effects. The standardized induction of neural form of transplanted ADSCs can lead to a future application in clinical practice.

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.

Sign in / Sign up

Export Citation Format

Share Document