Reduced cerebral blood flow in an α-synuclein transgenic mouse model of Parkinson’s disease

There is increasing evidence that widespread cortical cerebral blood flow deficits occur early in the course of Parkinson’s disease. Although cerebral blood flow measurement has been suggested as a potential biomarker for early diagnosis of Parkinson’s disease, as well as a means for tracking response to treatment, the relationship of cerebral blood flow to α-synucleinopathy, a major pathological hallmark of Parkinson’s disease, remains unclear. Therefore, we performed arterial spin-labeling magnetic resonance imaging and diffusion tensor imaging on transgenic mice overexpressing human wild-type α-synuclein and age-matched controls to measure cerebral blood flow and degenerative changes. As reported for early-stage Parkinson’s disease, α-synuclein mice exhibited a significant reduction in cortical cerebral blood flow, which was accompanied by motor coordination deficits and olfactory dysfunction. Although no overt degenerative changes were apparent in diffusion tensor imaging images, magnetic resonance imaging volumetric analysis revealed a significant reduction in olfactory bulb volume, similar to that seen in Parkinson’s disease patients. Our data, representing the first report of cerebral blood flow deficit in an animal model of Parkinson’s disease, suggest a causative role for α-synucleinopathy in cerebral blood flow deficits in Parkinson’s disease. Thus, α-synuclein transgenic mice comprise a promising model to study Parkinson’s disease-related mechanisms of cerebral blood flow deficits and to investigate further its utility as a potential biomarker for Parkinson’s disease.     

Possible role of glial cell line-derived neurotrophic factor for predicting cognitive impairment in Parkinson’s disease: a case-control study

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the protection of dopaminergic neurons, but there are few reports of the relationship between GDNF and its precursors (α-pro-GDNF and β-pro-GDNF) and cognitive impairment in Parkinson’s disease. This study aimed to investigate the relationship between the serum levels of GDNF and its precursors and cognitive impairment in Parkinson’s disease, and to assess their potential as a diagnostic marker. Fifty-three primary outpatients and hospitalized patients with Parkinson’s disease (23 men and 30 women) with an average age of 66.58 years were enrolled from the Affiliated Hospital of Xuzhou Medical University of China in this case-control study. The patients were divided into the Parkinson’s disease with cognitive impairment group (n = 27) and the Parkinson’s disease with normal cognitive function group (n = 26) based on their Mini-Mental State Examination, Montreal Cognitive Assessment, and Clinical Dementia Rating scores. In addition, 26 age- and sex-matched healthy subjects were included as the healthy control group. Results demonstrated that serum GDNF levels were significantly higher in the Parkinson’s disease with normal cognitive function group than in the other two groups. There were no significant differences in GDNF precursor levels among the three groups. Correlation analysis revealed that serum GDNF levels, GDNF/α-pro-GDNF ratios, and GDNF/β-pro-GDNF ratios were moderately or highly correlated with the Mini-Mental State Examination, Montreal Cognitive Assessment, and Clinical Dementia Rating scores. To explore the risk factors for cognitive impairment in patients with Parkinson’s disease, logistic regression analysis and stepwise linear regression analysis were performed. Both GDNF levels and Hoehn-Yahr stage were risk factors for cognitive impairment in Parkinson’s disease, and were the common influencing factors for cognitive scale scores. Neither α-pro-GDNF nor β-pro-GDNF was risk factors for cognitive impairment in Parkinson’s disease. A receiver operating characteristic curve of GDNF was generated to predict cognitive function in Parkinson’s disease (area under the curve = 0.859). This result indicates that the possibility that serum GDNF can correctly distinguish whether patients with Parkinson’s disease have cognitive impairment is 0.859. Together, these results suggest that serum GDNF may be an effective diagnostic marker for cognitive impairment in Parkinson’s disease. However, α-pro-GDNF and β-pro-GDNF are not useful for predicting cognitive impairment in this disease. This study was approved by Ethics Committee of the Affiliated Hospital of Xuzhou Medical University, China (approval No. XYFY2017-KL047-01) on November 30, 2017.

Chinese Library Classification No. R441; R447; R741     

Modulation of the Microbiome in Parkinson’s Disease: Diet,Drug, Stool Transplant,and Beyond

The gastrointestinal microbiome is altered in Parkinson’s disease and likely plays a key role in its pathophysiology, affecting symptoms and response to therapy and perhaps modifying progression or even disease initiation. Gut dysbiosis therefore has a significant potential as a therapeutic target in Parkinson’s disease, a condition elusive to disease-modifying therapy thus far. The gastrointestinal environment hosts a complex ecology, and efforts to modulate the relative abundance or function of established microorganisms are still in their infancy. Still, these techniques are being rapidly developed and have important implications for our understanding of Parkinson’s disease. Currently, modulation of the microbiome can be achieved through non-pharmacologic means such as diet, pharmacologically through probiotic, prebiotic, or antibiotic use and procedurally through fecal transplant. Novel techniques being explored include the use of small molecules or genetically engineered organisms, with vast potential. Here, we review how some of these approaches have been used to date, important areas of ongoing research, and how microbiome modulation may play a role in the clinical management of Parkinson’s disease in the future.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00942-2) contains supplementary material, which is available to authorized users.Key Words: Gastrointestinal microbiome, dysbiosis, Parkinson’s disease, therapy, diet, probiotics, fecal microbiota transplantation, organisms, genetically modified     

Growth differentiation factor 5: a neurotrophic factor with neuroprotective potential in Parkinson’s disease

Parkinson’s disease is the most common movement disorder worldwide, affecting over 6 million people. It is an age-related disease, occurring in 1% of people over the age of 60, and 3% of the population over 80 years. The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra, and their axons, which innervate the striatum, resulting in the characteristic motor and non-motor symptoms of Parkinson’s disease. This is paralleled by the intracellular accumulation of α-synuclein in several regions of the nervous system. Current therapies are solely symptomatic and do not stop or slow disease progression. One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum, to protect the remaining dopaminergic neurons of the nigrostriatal pathway. However, clinical trials of two well-established neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have failed to meet their primary end-points. This failure is thought to be at least partly due to the downregulation by α-synuclein of Ret, the common co-receptor of glial cell line-derived neurorophic factor and neurturin. Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors, that signals through the Ret-independent canonical Smad signaling pathway. Here, we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson’s disease. We discuss new work on growth/differentiation factor 5’s mechanisms of action, as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in the α-synuclein rat model of Parkinson’s disease. These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson’s disease.Key Words: adeno-associated virus, bone morphogenetic protein, dopaminergic neurons, growth/differentiation factor 5, neurodegeneration, neuroprotection, neurotrophic factor, Parkinson''s disease, Smad signaling, α-synuclein     

Motivational modes and learning in Parkinson’s disease

Learning and motivation are intrinsically related, and both have been linked to dopamine. Parkinson’s disease results from a progressive loss of dopaminergic inputs to the striatum and leads to impairments in motivation and learning from feedback. However, the link between motivation and learning in Parkinson’s disease is not well understood. To address this gap, we leverage a well-established psychological theory of motivation, regulatory mode theory, which distinguishes between two functionally independent motivational concerns in regulating behavior: a concern with having an effect by initiating and maintaining movement (Locomotion) and a concern with establishing what is correct by critically evaluating goal pursuit means and outcomes (Assessment). We examined Locomotion and Assessment in patients with Parkinson’s disease and age-matched controls. Parkinson’s disease patients demonstrated a selective decrease in Assessment motivation but no change in Locomotion motivation, suggesting that Parkinson’s disease leads to a reduced tendency to evaluate and monitor outcomes. Moreover, weaker Assessment motivation was correlated with poorer performance on a feedback-based learning task previously shown to depend on the striatum. Together, these findings link a questionnaire-based personality inventory with performance on a well-characterized experimental task, advancing our understanding of how Parkinson’s disease affects motivation with implications for well-being and treatment outcomes.     

From cradle to grave: neurogenesis,neuroregeneration and neurodegeneration in Alzheimer’s and Parkinson’s diseases

Two of the most common neurodegenerative disorders – Alzheimer’s and Parkinson’s diseases – are characterized by synaptic dysfunction and degeneration that culminate in neuronal loss due to abnormal protein accumulation. The intracellular aggregation of hyper-phosphorylated tau and the extracellular aggregation of amyloid beta plaques form the basis of Alzheimer’s disease pathology. The major hallmark of Parkinson’s disease is the loss of dopaminergic neurons in the substantia nigra pars compacta, following the formation of Lewy bodies, which consists primarily of alpha-synuclein aggregates. However, the discrete mechanisms that contribute to neurodegeneration in these disorders are still poorly understood. Both neuronal loss and impaired adult neurogenesis have been reported in animal models of these disorders. Yet these findings remain subject to frequent debate due to a lack of conclusive evidence in post mortem brain tissue from human patients. While some publications provide significant findings related to axonal regeneration in Alzheimer’s and Parkinson’s diseases, they also highlight the limitations and obstacles to the development of neuroregenerative therapies. In this review, we summarize in vitro and in vivo findings related to neurogenesis, neuroregeneration and neurodegeneration in the context of Alzheimer’s and Parkinson’s diseases.Key Words: alpha-synuclein, amyloid beta plaques, autophagy, dopaminergic neurons, human iPSCs, mitochondrial dysfunction, scRNA sequencing, synaptic dysfunction, Tau, Wallerian degeneration     

Neuroprotective mechanisms of ε-viniferin in a rotenone-induced cell model of Parkinson's disease: significance of SIRT3-mediated FOXO3 deacetylation

Trans-(-)-ε-viniferin (ε-viniferin) has antioxidative and anti-inflammatory effects. It also has neuroprotective effects in Huntington’s disease by activating the SIRT3/LKB1/AMPK signaling pathway; however, it remains unknown whether ε-viniferin also has a neuroprotective role in Parkinson’s disease. A Parkinson’s disease cell model was induced by exposing SH-SY5Y cells to 3.0 μM rotenone for 24 hours, and cells were then treated with 1.0 μM ε-viniferin for 24 hours. Treatment with ε-viniferin upregulated SIRT3 expression, which promoted FOXO3 deacetylation and nuclear localization. ε-Viniferin also increased ATP production and decreased reactive oxygen species production. Furthermore, ε-viniferin treatment alleviated rotenone-induced mitochondrial depolarization and reduced cell apoptosis, and restored the expression of mitochondrial homeostasis-related proteins. However, when cells were transfected with SIRT3 or FOXO3 shRNA prior to rotenone and ε-viniferin treatment, these changes were reversed. The results from the present study indicate that ε-viniferin enhances SIRT3-mediated FOXO3 deacetylation, reduces oxidative stress, and maintains mitochondrial homeostasis, thus inhibiting rotenone-induced cell apoptosis. ε-Viniferin may therefore be a promising treatment strategy for Parkinson’s disease.

Chinese Library Classification No. R453; R363; R741     

Ceftriaxone Blocks the Polymerization of α-Synuclein and Exerts Neuroprotective Effects in Vitro

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Lipopolysaccharide mouse models for Parkinson’s disease research: a critical appraisal

Parkinson’s disease, the most common movement disorder, has a strong neuroinflammatory aspect. This is evident by increased pro-inflammatory cytokines in the serum, and the presence of activated microglial cells, and inflammatory cytokines in the substantia nigra of post-mortem brains as well as cerebrospinal fluid of Parkinson’s disease patients. The central and peripheral neuroinflammatory aspects of Parkinson’s disease can be investigated in vivo via administration of the inflammagen lipopolysaccharide, a component of the cell wall of gram-negative bacteria. In this mini-review, we will critically evaluate different routes of lipopolysaccharide administration (including intranasal systemic and stereotasic), their relevance to clinical Parkinson’s disease as well as the recent findings in lipopolysaccharide mouse models. We will also share our own experiences with systemic and intrastriatal lipopolysaccharide models in C57BL/6 mice and will discuss the usefulness of lipopolysaccharide mouse models for future research in the field.Key Words: C57BL/6 mice, intranasal models, lipopolysaccharide models, neuroinflammation, Parkinson’s disease, stereotaxic models, substantia nigra, systemic models     

Rotigotine transdermal system: a short review

Rotigotine (Neupro^®) is a new non-ergolinic dopamine agonist transdermal patch that can be applied once daily. To date, it is approved for the treatment of early Parkinson’s disease as monotherapy and has been shown to be effective in the treatment of advanced-stage Parkinson’s disease and restless legs syndrome in several clinical trials. This review gives an overview of physical, chemical, and pharmaceutical characteristics, pharmacokinetics, biotransformation and elimination, drug interactions, and adverse events of rotigotine. Further, the rationale for the treatment of Parkinson’s disease and restless legs syndrome with rotigotine is discussed.     

Imaging Familial and Sporadic Neurodegenerative Disorders Associated with Parkinsonism

In this paper, the structural and functional imaging changes associated with sporadic and genetic Parkinson’s disease and atypical Parkinsonian variants are reviewed. The role of imaging for supporting diagnosis and detecting subclinical disease is discussed, and the potential use and drawbacks of using imaging biomarkers for monitoring disease progression is debated. Imaging changes associated with nonmotor complications of PD are presented. The similarities and differences in imaging findings in Lewy body dementia, Parkinson’s disease dementia, and Alzheimer’s disease are discussed.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00994-4.     

LRRK2 Ablation Attenuates Αlpha-Synuclein–Induced Neuroinflammation Without Affecting Neurodegeneration or Neuropathology In Vivo

The development of disease-modifying therapies for Parkinson’s disease is a major challenge which would be facilitated by a better understanding of the pathogenesis. Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are key players in Parkinson’s disease, but their relationship remains incompletely resolved. Previous studies investigating the effect of LRRK2 on α-synuclein–induced neurotoxicity and neuroinflammation in preclinical Parkinson’s disease models have reported conflicting results. Here, we aimed to further explore the functional interaction between α-synuclein and LRRK2 and to evaluate the therapeutic potential of targeting physiological LRRK2 levels. We studied the effects of total LRRK2 protein loss as well as pharmacological LRRK2 kinase inhibition in viral vector–mediated α-synuclein–based Parkinson’s disease models developing early- and late-stage neurodegeneration. Surprisingly, total LRRK2 ablation or in-diet treatment with the LRRK2 kinase inhibitor MLi-2 did not significantly modify α-synuclein–induced motor deficits, dopaminergic cell loss, or α-synuclein pathology. Interestingly, we found a significant effect on α-synuclein–induced neuroinflammatory changes in the absence of LRRK2, with a reduced microglial activation and CD4⁺ and CD8⁺ T cell infiltration. This observed lack of protection against α-synuclein–induced toxicity should be well considered in light of the ongoing therapeutic development of LRRK2 kinase inhibitors for idiopathic Parkinson’s disease. Future studies will be crucial to understand the link between these neuroinflammatory processes and disease progression as well as the role of α-synuclein and LRRK2 in these pathological events.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01007-8.Key Words: Leucine-rich repeat kinase 2, alpha-synuclein, Parkinson’s disease, neuroinflammation, kinase inhibition     

Optimization of 6-Heterocyclic-2-(1H-pyrazol-1-yl)-N-(pyridin-2-yl)pyrimidin-4-amine as Potent Adenosine A2A Receptor Antagonists for the Treatment of Parkinson’s Disease

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Endogenous versus exogenous cell replacement for Parkinson’s disease: where are we at and where are we going?

Parkinson’s disease is the second most common neurodegenerative disease and has currently no effective treatment, one that would be able to stop or reverse the loss of dopaminergic neurons in the substantia nigra pars compacta. In addition, Parkinson’s disease diagnosis is typically done when a significant percentage of the dopaminergic neurons is already lost. In neurodegenerative disorders, some therapeutic strategies could be effective only at inhibiting further degeneration; on the other hand, cell replacement therapies aim at replacing lost neurons, an approach that would be ideal for the treatment of Parkinson’s disease. Many cell replacement therapies have been tested since the 1970s in the field of Parkinson’s disease; however, there are still significant limitations prohibiting a successful clinical application. From the first fetal midbrain intrastriatal graft to the most recent conversion of astrocytes into dopaminergic neurons, we have gained equally, significant insights and questions still looking for an answer. This review aims to summarize the main milestones in cell replacement approaches against Parkinson’s disease. By focusing on achievements and failures, as well as on the additional research steps needed, we aim to provide perspective on how future cell replacement therapies treats Parkinson’s disease.Key Words: endogenous, neurodegenerative disease, neurogenesis, neurotrophic factors, Parkinson’s disease, stem cells, transdifferentiation, transplantations     

The Use of Pharmacological Retromer Chaperones in Alzheimer’s Disease and other Endosomal-related Disorders

The retromer is an evolutionary conserved multiprotein complex involved in the sorting and retrograde trafficking of cargo from endosomal compartments to the Golgi network and to the cell surface. The neuronal retromer traffics the amyloid precursor protein away from the endosomes, a site where amyloid precursor protein is enzymatically cleaved into pathogenic fragments in Alzheimer’s disease. In recent years, deficiencies in retromer-mediated transport have been implicated in several neurological and non-neurological diseases, including Parkinson’s disease, suggesting that improving the efficacy of the retromer trafficking pathway would result in decreased pathology. We recently identified a new family of small molecules that appear to stabilize the interaction between members of the retromer complex and enhance its function in neurons: the retromer pharmacological chaperones. Here we discuss the role of these molecules in the improvement of retromer trafficking and endosomal dysfunction, as well as their potential as therapeutics for neurological and non-neurological disorders.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-014-0321-y) contains supplementary material, which is available to authorized users.Key Words: Retromer, Alzheimer’s disease, neurodegeneration, pharmacological chaperones     

Human Pluripotent Stem Cell Therapy for Huntington’s Disease: Technical,Immunological, and Safety Challenges

Intra-striatal transplantation of homotypic fetal tissue at the time of peak striatal neurogenesis can provide some functional benefit to patients suffering from Huntington’s disease. Currently, the only approach shown to slow down the course of this condition is replacement of the neurons primarily targeted in this disorder, although it has been transient and has only worked with a limited number of patients. Otherwise, this dominantly inherited neurodegenerative disease inevitably results in the progressive decline of motricity, cognition, and behavior, and leads to death within 15 to 20 years of onset. However, fetal neural cell therapy of Huntington’s disease, as with a similar approach in Parkinson’s disease, is marred with both technical and biological hurdles related to the source of grafting material. This heavily restricts the number of patients who can be treated. A substitute cell source is therefore needed, but must perform at least as well as fetal neural graft in terms of brain recovery and reconstruction, while overcoming its major obstacles. Human pluripotent stem cells (embryonic in origin or induced from adult cells through genetic reprogramming) have the potential to meet those challenges. In this review, the therapeutic potential in view of 4 major issues is identified during fetal cell therapy clinical trials: 1) logistics of graft procurement, 2) quality control of the cell preparation, 3) immunogenicity of the graft, and 4) safety of the procedure.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-011-0079-4) contains supplementary material, which is available to authorized users.     

Parkinson’s disease and diabetes mellitus: common mechanisms and treatment repurposing

In the last decade, attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system, as insulin in the brain is implicated in neuronal survival, plasticity, oxidative stress and neuroinflammation. Diabetes mellitus and Parkinson’s disease are both aging-associated diseases that are turning into epidemics worldwide. Diabetes mellitus and insulin resistance not only increase the possibility of developing Parkinson’s disease but can also determine the prognosis and progression of Parkinsonian symptoms. Today, there are no available curative or disease modifying treatments for Parkinson’s disease, but the role of insulin and antidiabetic medications in neurodegeneration opens a door to treatment repurposing to fight against Parkinson’s disease, both in diabetic and nondiabetic Parkinsonian patients. Furthermore, it is essential to comprehend how a frequent and treatable disease such as diabetes can influence the progression of neurodegeneration in a challenging disease such as Parkinson’s disease. Here, we review the present evidence on the connection between Parkinson’s disease and diabetes and the consequential implications of the existing antidiabetic molecules in the severity and development of Parkinsonism, with a particular focus on glucagon-like peptide-1 receptor agonists.Key Words: antidiabetic, diabetes mellitus, dopamine, exenatide, glucagon-like peptide-1, insulin, neurodegeneration, neuroinflammation, Parkinson''s disease, repurposing     

Potential therapeutic effects of polyphenols in Parkinson's disease: in vivo and in vitro pre-clinical studies

Parkinson's disease is a neurodegenerative disorder characterized by a combination of severe motor and non-motor symptoms. Over the years, several factors have been discovered to play a role in the pathogenesis of this disease, in particular, neuroinflammation and oxidative stress. To date, the pharmacological treatments used in Parkinson's disease are exclusively symptomatic. For this reason, in recent years, the research has been directed towards the discovery and study of new natural molecules to develop potential neuroprotective therapies against Parkinson's disease. In this context, natural polyphenols have raised much attention for their important anti-inflammatory and antioxidant properties, but also for their ability to modulate protein misfolding. In this review, we propose to summarize the relevant in vivo and in vitro studies concerning the potential therapeutic role of natural polyphenols in Parkinson's disease.     

Imaging of Superoxide Generation in the Dopaminergic Area of the Brain in Parkinson’s Disease,Using Mito-TEMPO

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