Oxidative stress and neuroinflammation in the story of Parkinson’s disease: Could targeting these pathways write a good ending?

Although, current medications for Parkinson’s disease can control and relief symptoms of the disease efficiently, they are unable to either prevent progression of the disease or maintain their controlling ability as a long-term medication. To find suitable adjuvant and/or alternative treatments, researchers have investigated antioxidative and anti-inflammatory approaches, since emerging evidence consider oxidative stress and neuroinflammation as leading causes of the development of Parkinson’s disease. Here, how oxidative stress and neuroinflammation take part in Parkinson’s disease pathogenesis was discussed based on featured studies in this context. Then, preclinical and clinical trial studies, which evaluated antioxidative and anti-inflammatory compounds’ ability to treat Parkinson’s disease, were reviewed.     

Imagerie moléculaire de la maladie de Parkinson : données actuelles

During the last years, knowledge and concepts concerning Parkinson's disease and other parkinsonian syndromes have progressed: a concept of network pathology with different clinical presentations and evolutions, involving several neurotransmission pathways succeeeded the single dopaminergic lesion concept. Imaging also changed with the development of MRI. In this context, the aim of this work is to bring up-to-date methodology and clinical contribution of dopaminergic neuron imaging. Nigrostriatal neuron imaging (dopamine transporter imaging) contributes to diagnosis of Parkinson's disease and Lewy body dementia. Dopamine receptor imaging mainly helps in differential diagnosis of parkinsonian syndromes (Parkinson's disease and Parkinson plus syndromes). The ongoing development of dopaminergic, cholinergic, serotoninergic tracers and the recent emergence of amyloid plaques and neurofibrillary tangles imaging open perspectives for molecular imaging and care of neurodegenerative diseases.     

Parkinson’s disease and risk of prostate cancer: A Danish population-based case-control study, 1995–2010

IntroductionProstate cancer growth and progression may be linked to neurogenesis and to medical anti- Parkinson treatment, but results are inconclusive. Therefore, we examined the association between Parkinson’s disease and risk of prostate cancer in a population based case-control study.MethodsWe identified 45,429 patients diagnosed with incident prostate cancer during 1997–2010 from the National Cancer Registry. Five age-matched population controls (n = 227,145) were selected for each case. Odds ratios (ORs) adjusted for age and comorbidity for prostate cancer associated with Parkinson’s disease were computed using conditional logistic regression. Analyses were stratified by duration of Parkinson’s disease and stage of prostate cancer (localized and advanced).ResultsIn total, 245 patients (0,5%) and 1656 controls (0,7%) had Parkinson’s disease. Overall, patients with Parkinson’s disease had a 27% lower risk of prostate cancer compared with patients without Parkinson’s disease (adjusted OR (ORa) 0.73; 95% confidence interval (CI), 0.63–0.83).Risk of prostate cancer decreased with increasing duration of Parkinson’s disease.The odds ratios were slightly lower for advanced prostate cancer (ORa, 0.68; 95% CI, 0.52–0.88) than for localized prostate cancer (ORa 0.76; 95% CI, 0.61–0.93).ConclusionParkinson’s disease was associated with a risk reduction overall (27%), which decreased with increasing duration of Parkinson’s disease.     

Molecular genetics of Parkinson’s disease

The current views on the role of genetic factors in the pathogenesis of Parkinson’s disease are considered. The review is focused on monogenic forms of the disease, for which 11 loci are mapped and seven genes whose mutations cause the disease are identified. In addition, a number of candidate genes for sporadic Parkinson’s disease are described. The further development of studying genetic bases of Parkinson’s disease will follow two main directions: in-depth analysis of genes related to the monogenic form of the disease and more large-scale associative investigation of candidate genes for the sporadic form of Parkinson’s disease.     

The Expression and Release of Hsp60 in 6-OHDA Induced In Vivo and In Vitro Models of Parkinson’s Disease

In Parkinson’s disease, dopaminergic neuron damage/death causes the release of soluble substances that are selectively toxic to neighboring/additional dopaminergic neurons through the activation of microglia. Hsp60 can be released from injured cells of central nervous system to activate microglia. However, its expression and role in Parkinson’s disease has not been well understood. Here, we performed a 6-OHDA treated Parkinson’s disease model in adult rats. Western blot analysis showed a time-course expression of Hsp60, which decreased gradually and then rose back. Immunofluorescence staining showed that Hsp60 was decreased in dopaminergic neuron, and most Hsp60 located on the surface of activated microglia. Furthermore, in cellular Parkinson’s disease model, Hsp60 was obviously detected in the culture supernatants after 6-OHDA treatment, and a concomitant decrease in cell extracts. Taken together, our results suggested that Hsp60 could be released extracellularly to activate microglia in Parkinson’s disease model.     

2D gel blood serum biomarkers reveal differential clinical proteomics of the neurodegenerative diseases

This review addresses the challenges of neuroproteomics and recent progress in biomarkers and tests for neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. The review will discuss how the application of quantitative 2D gel electrophoresis, combined with appropriate single-variable and multivariate biostatistics, allows for selection of disease-specific serum biomarkers. It will also address how the use of large cohorts of specifically targeted patient blood serum samples and complimentary age-matched controls, in parallel with the use of selected panels of these biomarkers, are being applied to the development of blood tests to specifically address unmet pressing needs in the differential diagnosis of these diseases, and to provide potential avenues for mechanism-based drug targeting and treatment monitoring. While exploring recent findings in this area, the review discusses differences in critical pathways of immune/inflammation and amyloid formation between Parkinson’s disease and amyotrophic lateral sclerosis, as well as discernable synergistic relationships between these pathways that are revealed by this approach. The potential for pathway measurement in blood tests for differential diagnosis, disease burden and therapeutic monitoring is also outlined.     

Genetik der Parkinson-Krankheit

In addition to the nine well-defined monogenic forms of Parkinson’s disease, there are numerous known genetic risk and protective variants that modulate the risk of Parkinson’s disease. Among the monogenic forms, three (PARK1/PARK4, PARK8, PARK17) follow an autosomal dominant mode of inheritance, whereas six are recessively inherited (PARK2, PARK6, PARK7, PARK9, PARK14, PARK15). Six forms have clinical characteristics very similar to those of idiopathic Parkinson’s disease (PARK1/PARK4, PARK2, PARK6, PARK7, PARK8, PARK17). Among the latter forms, late-onset PARK8 with mutations in the LRRK2 gene and early-onset PARK2 caused by mutations in the Parkin gene are by far the most common. Both the monogenic and the idiopathic forms of Parkinson’s disease share common pathophysiological mechanisms involving oxidative modification, impaired protein degradation and mitochondrial dysfunction. Therefore, monogenic forms of Parkinson’s disease can serve as human model diseases for the idiopathic forms.     

Parkinson disease drug screening based on the interaction between D2 dopamine receptor and beta-arrestin 2 detected by capillary zone electrophoresis

Parkinson’s disease is the second most common neurodegenerative disease in the world. Beta-arrestin-2 has been reported to be an important protein involved in D₂ dopamine receptor desensitization, which is essential to Parkinson’s disease. Moreover, the potential value of pharmacological inactivation of G protein-coupled receptor kinase or arrestin in the treatment of patients with Parkinson’s disease has recently been shown. We studied the interaction between D₂ dopamine receptor and beta-arrestin-2 and the pharmacological regulation of chemical compounds on such interaction using capillary zone electrophoresis. The results from screening more than 40 compounds revealed three compounds that remarkably inhibit the beta-arrestin-2/D₂ dopamine receptor interaction among them. These compounds are promising therapies for Parkinson’s disease, and the method used in this study has great potential for application in large-scale drug screening and evaluation.     

EMG signal morphology and kinematic parameters in essential tremor and Parkinson’s disease patients

The aim of this work was to differentiate patients with essential tremor from patients with Parkinson’s disease. Electromyographic data from biceps brachii muscles and kinematic data from arms during isometric tension of the arms were measured from 17 patients with essential tremor, 35 patients with Parkinson’s disease and 40 healthy controls.The EMG signals were divided to smaller segments from which histograms were calculated. The histogram shape was analysed with a feature dimension reduction method, the principal component analysis, and the shape parameters were used to differentiate between different subject groups. Three parameters, RMS-amplitude, sample entropy and peak frequency were determined from the kinematic measurements of the arms.The height and the side differences of the histogram were the most effective for differentiating between essential tremor and Parkinson’s disease groups. The histogram parameters of patients with essential tremor were more similar to patients with Parkinson’s disease than healthy controls. With this method it was possible to discriminate 13/17 patients with essential tremor from 26/35 patients with Parkinson’s disease and 14/17 patients with essential tremor from 29/40 healthy controls. The kinematic parameters of patients with essential tremor were closer to parameters of patients with Parkinson’s disease compared to healthy controls. Combining EMG and kinematic analysis did not increase discrimination efficiency but provided more reliability to the discrimination of subject groups.     

Systemic neurophysiological analysis of Parkinson’s disease

On the basis of comprehensive neurophysiological examination, we tried to analyze the systemic organization of functions in Parkinson’s disease in terms of the theory of functional systems. Study of the specificity of internal neurophysiological organization helps to find a high level of internal tension and limitation of functional reserves in patients with Parkinson’s disease, including those with the rigid form and long duration of the disease. The possible predominance of homeostatic response programs in Parkinson’s disease is discussed.     

Multimodal retinal imaging to detect and understand Alzheimer’s and Parkinson’s disease

Retinal neurodegeneration and visual dysfunctions have been reported in a majority of Alzheimer’s and Parkinson’s patients, and, in light of the quest for novel biomarkers for these neurodegenerative proteinopathies, the retina has been receiving increasing attention as an organ for diagnosing, monitoring, and understanding disease. Thinning of retinal layers, abnormalities in vasculature, and protein deposition can be imaged at unprecedented resolution, which offers a unique systems biology view on the cellular and molecular changes underlying these pathologies. It makes the retina not only a promising target for biomarker development, but it also suggests that novel fundamental insights into the pathophysiology of Alzheimer’s and Parkinson’s disease can be obtained by studying the retina–brain axis.     

Mitochondrial dysfunction in protein conformational disorders

Protein aggregation is a hallmark of many neurodegenerative diseases. In Parkinson’s disease protein misfolding of \(\upalpha \)-synuclein involves conformational changes in the protein structure that often results in self-association and aggregation leading to accumulation of \(\upalpha \)-synuclein in neuronal cells. The underlying mechanisms by which aggregations can lead to impaired cellular functions are often not understood. Meanwhile, there is growing evidence that links mitochondrial dysfunction to Parkinson’s disease. As both mitochondria and protein aggregation of \(\upalpha \)-synuclein have been shown to play a major role in Parkinson’s disease, it seems likely that a converging mechanism exists that links the two pathways.     

The Ceruloplasmin Transferrin Ratio in the Blood of Patients at Different Stages of Parkinson’s Disease

The ratio of the concentrations of Cu²⁺-ceruloplasmin/Fe³⁺-transferrin in the blood plasma of 54 patients at different stages of Parkinson’s disease treated and not treated with L-DOPA was estimated by EPR-spectroscopy. It was established that in patients who suffer from Parkinson’s disease, the value of ceruloplasmin/ transferrin increased by 157% in comparison with the control group of clinically healthy people of the same age group. In patients with Parkinson’s disease, the ratio of ceruloplasmin/transferrin increased at stage 1 of the disease by 119%, at stage 2 by 117%, and at stage 3 by 135% in comparison with the control group. There was no statistically significant difference between the ratio of ceruloplasmin/transferrin in patients who received and did not recive L-DOPA replacement therapy. These data reveal changes in the functioning of the ceruloplasmin: transferrin system, which decreases the content of toxic ions of Fe²⁺ in the plasma of patients with Parkinson’s disease. These changes are a pathogenetically significant factor of Parkinson’s disease at all stages of the disease.     

Role of Autophagy Pathway in Parkinson’s Disease and Related Genetic Neurological Disorders

The elucidation of the function of the PINK1 protein kinase and Parkin ubiquitin E3 ligase in the elimination of damaged mitochondria by autophagy (mitophagy) has provided unprecedented understanding of the mechanistic pathways underlying Parkinson’s disease (PD). We provide a comprehensive overview of the general importance of autophagy in Parkinson’s disease and related disorders of the central nervous system. This reveals a critical link between autophagy and neurodegenerative and neurodevelopmental disorders and suggests that strategies to modulate mitophagy may have greater relevance in the CNS beyond PD.     

New Insight into Neurodegeneration: the Role of Proteomics

Recent advances within the field of proteomics, including both upstream and downstream protocols, have fuelled a transition from simple protein identification to functional analysis. A battery of proteomics approaches is now being employed for the analysis of protein expression levels, the monitoring of cellular activities and for gaining an increased understanding into biochemical pathways. Combined, these approaches are changing the way we study disease by allowing accurate and targeted, large scale protein analysis, which will provide invaluable insight into disease pathogenesis. Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), prion disease, and other diseases that affect the neuromuscular system, are a leading cause of disability in the aging population. There are no effective intervention strategies for these disorders and diagnosis is challenging as it relies primarily on clinical symptomatic features, which often overlap at early stages of disease. There is, therefore, an urgent need to develop reliable biomarkers to improve early and specific diagnosis, to track disease progression, to measure molecular responses towards treatment regimes and ultimately devise new therapeutic strategies. To accomplish this, a better understanding of disease mechanisms is needed. In this review we summarize recent advances in the field of proteomics applicable to neurodegenerative disorders, and how these advances are fueling our understanding, diagnosis, and treatment of these complex disorders.     

Water-Soluble Coenzyme Q10 Reduces Rotenone-Induced Mitochondrial Fission

Parkinson’s disease is a neurodegenerative disorder characterized by mitochondrial dysfunction and oxidative stress. It is usually accompanied by an imbalance in mitochondrial dynamics and changes in mitochondrial morphology that are associated with impaired function. The objectives of this study were to identify the effects of rotenone, a drug known to mimic the pathophysiology of Parkinson’s disease, on mitochondrial dynamics. Additionally, this study explored the protective effects of water-soluble Coenzyme Q10 (CoQ10) against rotenone-induced cytotoxicity in murine neuronal HT22 cells. Our results demonstrate that rotenone elevates protein expression of mitochondrial fission markers, Drp1 and Fis1, and causes an increase in mitochondrial fragmentation as evidenced through mitochondrial staining and morphological analysis. Water-soluble CoQ10 prevented mitochondrial dynamic imbalance by reducing Drp1 and Fis1 protein expression to pre-rotenone levels, as well as reducing rotenone treatment-associated mitochondrial fragmentation. Hence, water-soluble CoQ10 may have therapeutic potential in treating patients with Parkinson’s disease.     

Rivastigmine als ondersteuning bij het dilemma van de behandeling van hallucinaties optredend bij ziekte van Parkinson

We report three cases of patients with Parkinson’s disease without dementia, admitted to our hospital because of hallucinations. The anti-Parkinson medication was adapted and the patients started with rivastigmine. As a result, hallucinations no longer occurred. A 79 years old man also required short-term quetiapine because of agitation and anti-Parkinson doses were without side effects, as a result of which mobility improved. An 84 years old woman reported mild side effects of rivastigmine, without consequences, whereas her mobility appeared to be good. A 72 years old woman reported mild memory problems upon admission, which improved during admission, as did her mobility after increasing the anti-Parkinson medication doses. Treatment of rivastigmine can be useful in the therapeutic dilemma in the treatment of hallucinations in patients with Parkinson’s disease (start anti-psychotic or reduce anti-Parkinson medication). In addition to adapting anti-Parkinson doses and sometimes short-term treating with an anti-psychotic, treatment with rivastigmine appears to be a quick improvement, without serious side effects. Also, mobility can improve, due to the possibility of increasing the anti-Parkinson doses, if necessary. Because of the many remaining questions, prospective randomised trials are needed.     

溶酶体跨膜蛋白175钾通道蛋白质与帕金森病

帕金森病(Parkinson’s disease,PD)是一种复杂的神经退行性疾病,以运动障碍和非运动症状为特征。虽然以多巴胺为基础的疗法在疾病的早期阶段能有效地对抗症状,但缺乏神经保护药物意味着疾病仍在继续发展。PD病人迫切需要新的疾病修饰疗法和新的治疗策略。遗传学研究表明,罕见和常见的基因变异都会导致PD的发生和发展。跨膜蛋白175(transmembrane protein 175,TMEM175)是来自溶酶体的PD风险基因之一,编码一种具有新型结构的溶酶体钾通道蛋白质,参与维持溶酶体膜电位和pH的稳定性。随着对TMEM175的了解,多项研究证实TMEM175的缺陷能够导致溶酶体功能障碍,诱导神经元α-突触核蛋白(α-synuclein)的病理性聚集,促进帕金森病发生。鉴于溶酶体TMEM175通道蛋白的重要功能,TMEM175基因可能是帕金森病及其他神经退行性疾病治疗的潜在靶点。本文综述了溶酶体TMEM175基因的结构及功能,重点阐述了其作为溶酶体内稳态调节因子通过影响溶酶体的功能参与PD发生发展的过程,并对其研究进行了展望。以TMEM175为靶标,筛选具有保持TMEM175的活性状态或增强其表达的药物可能具有改善PD病人病情的效果,但TMEM175如何通过保持其通道的开放和闭合状态之间的平衡来调节溶酶体的离子稳态,具体机制尚需要进一步研究探讨。未来对该离子通道蛋白质的进一步研究将为 靶向PD治疗带来新的策略和思路,为在PD的诊断与治疗中奠定TMEM175的靶标分子地位提供支持。     

Study protocol of “CHAPS”: a randomized controlled trial protocol of Care Coordination for Health Promotion and Activities in Parkinson’s Disease to improve the quality of care for individuals with Parkinson’s disease

Background

Parkinson’s disease, the second most common neurodegenerative disease, is diagnostically defined by motor impairments, but also includes often under-recognized impairments in cognition, mood, sleep, and the autonomic nervous system. These problems can severely affect individuals’ quality of life. In our prior research, we have developed indicators to measure the quality of care delivered to patients with Parkinson’s disease, and we identified gaps in delivering evidence-based treatments for this population. Effective strategies to close these gaps are needed to improve patient quality of life.

Methods/design

Building on prior research we developed a multi-faceted proactive implementation program called Care Coordination for Health Promotion and Activities in Parkinson’s Disease (CHAPS). To be eligible, patients had to have at least two visits with a primary diagnosis of idiopathic Parkinson’s disease (ICD-9 code: 332.0) at one of five Veterans Affairs Medical Centers in the southwestern United States from 2010 to 2014. The program consists of telephone assessments, evidence-based protocols, and tools to enhance patient self-management, care planning, and coordination of care across providers, including an electronic database to support and track coordination of care. Our mixed-methods study employs a randomized, controlled trial design to test whether the CHAPS intervention improves performance in 38 quality measures among an analytic sample of 346 patients. The 38 quality measures are categorized into overarching areas of communication, education, and continuity; regulatory reporting; diagnosis; periodic assessment; medication use; management of motor and non-motor symptoms; use of non-pharmacological approaches and therapies; palliative care; and health maintenance. Secondary outcomes are patient health-related quality of life, self-efficacy, and perceptions of care quality. We are also evaluating the extent of the CHAPS Program implementation and measuring program costs and impacts on health services utilization, in order to perform a analysis of the CHAPS program from the perspective of the Veterans Health Administration (VA). Outcomes are assessed by interviewer-administered surveys collected at baseline and at 6, 12, and 18 months, and by medical record chart abstractions. Analyses will be intention-to-treat.

Discussion

The CHAPS Program is poised for dissemination within the VA National Parkinson’s Disease Research, Education, and Clinical Center Consortium if demonstrated efficacious.

Trial Registration

ClinicalTrials.gov NCT01532986; registered on January 13, 2012.

     

Mitochondrial dysfunction and oxidative damage in the molecular pathology of Parkinson’s disease

Parkinson’s disease is a complex disorder that is characterized by progressive degeneration of nigrostriatal dopaminergic neurons. Its development is determined by the interaction between the genetic constitution of a body and environmental factors. Analysis of the genes associated with monogenic forms of Parkinson’s disease implicated proteasomal degradation, differentiation of dopaminergic neurons, mitochondrial dysfunction, and oxidative damage in its pathogenesis. The review considers ample data that suggest a key role for mitochondrial dysfunction and oxidative stress.