scholarly journals Long-Term Hyperglycemia Induces α-Synuclein Aggregation and Dopaminergic Neuronal Loss in Parkinson's Disease Mouse Model

2021 ◽  
Author(s):  
Yi-Qing Lv ◽  
Lin Yuan ◽  
Yan Sun ◽  
Hao-Wen Dou ◽  
Ji-Hui Su ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Loss ◽  
Underlying Mechanism ◽  
Alpha Synuclein ◽  
Cellular Level ◽  
Islet Amyloid ◽  
Nigrostriatal Degeneration

Abstract Background: Growing evidence suggest the association between Parkinson’s disease (PD) and diabetes mellitus (DM). On a cellular level, it was proven that long-term elevated levels of glucose might lead to nigrostriatal degeneration in PD models. However, the underlying mechanism is still unclear. Previously, we have elucidated the potential of type 2 diabetes mellitus (T2DM) in facilitating PD progression, involving aggregation of both alpha-synuclein (α-syn) and islet amyloid polypeptide (IAPP) in the pancreatic and brain tissues. However, due to the complicated effect of insulin resistance on PD onset, the actual mechanism of hyperglycemia-induced dopaminergic degeneration remains unknown. Methods: In the present study, we employed the type 1 diabetes mellitus (T1DM) model induced by streptozotocin (STZ) injection, to investigate the direct effect of elevated blood glucose level on nigrostriatal degeneration. Results: We found that STZ treatment induced more severe pathological alterations in the pancreatic islets and T1DM symptoms in α-syn-overexpression mice than that in wild type (WT) mice, one month and three months after STZ injections. Behavioral tests evaluating motor performance confirmed the nigrostriatal degeneration. Furthermore, we observed a marked decrease in dopaminergic profiles and an increase of α-syn accumulation and Serine 129 (S129) phosphorylation in STZ-treated α-syn mice compared with vehicle-treated mice. At last, we observed more severe neuroinflammation in the brain of the STZ-treated α-syn mice.Conclusion: Our results solidify the potential link between DM and PD, providing insights on how hyperglycemia induces nigrostriatal degeneration and contributes to pathogenetic mechanisms in PD.

scholarly journals Rab27 GTPases regulate alpha-synuclein uptake, cell-to-cell transmission, and toxicity

2020 ◽  
Author(s):  
Rachel Underwood ◽  
Bing Wang ◽  
Aneesh Pathak ◽  
Laura Volpicelli-Daley ◽  
Talene A. Yacoubian
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Alpha Synuclein ◽  
Rab Gtpases ◽  
Double Knockout ◽  
The Impact

SUMMARYParkinson’s disease and Dementia with Lewy Bodies are two common neurodegenerative disorders marked by proteinaceous aggregates composed primarily of the protein α-synuclein. α-Synuclein is hypothesized to have prion-like properties, by which misfolded α-synuclein induces the pathological aggregation of endogenous α-synuclein and neuronal loss. Rab27a and Rab27b are two highly homologous Rab GTPases that regulate α-synuclein secretion, clearance, and toxicity in vitro. In this study, we tested the impact of Rab27a/b on the transmission of pathogenic α-synuclein. Double knockout of both Rab27 isoforms eliminated α-synuclein aggregation and neuronal toxicity in primary cultured neurons exposed to fibrillary α-synuclein. In vivo, Rab27 double knockout mice lacked fibril-induced α-synuclein inclusions, dopaminergic neuron loss, and behavioral deficits seen in wildtype mice with fibril-induced inclusions. Studies using AlexaFluor488-labeled α-synuclein fibrils revealed that Rab27a/b knockout prevented α-synuclein internalization without affecting bulk endocytosis. Rab27a/b knockout also blocked the cell-to-cell spread of α-synuclein pathology in multifluidic, multichambered devices. This study provides critical insight into the role of Rab GTPases in Parkinson’s disease and identifies Rab27s as key players in the progression of synucleinopathies.

scholarly journals Acylated Ghrelin as a Multi-Targeted Therapy for Alzheimer's and Parkinson's Disease

2020 ◽  
Vol 14 ◽  
Author(s):  
Niklas Reich ◽  
Christian Hölscher
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Degeneration ◽  
Alpha Synuclein ◽  
Acylated Ghrelin ◽  
Therapeutic Benefits ◽  
Term Administration ◽  
The Impact ◽  
Impaired Neurogenesis

Much thought has been given to the impact of Amyloid Beta, Tau and Alpha-Synuclein in the development of Alzheimer's disease (AD) and Parkinson's disease (PD), yet the clinical failures of the recent decades indicate that there are further pathological mechanisms at work. Indeed, besides amyloids, AD and PD are characterized by the culminative interplay of oxidative stress, mitochondrial dysfunction and hyperfission, defective autophagy and mitophagy, systemic inflammation, BBB and vascular damage, demyelination, cerebral insulin resistance, the loss of dopamine production in PD, impaired neurogenesis and, of course, widespread axonal, synaptic and neuronal degeneration that leads to cognitive and motor impediments. Interestingly, the acylated form of the hormone ghrelin has shown the potential to ameliorate the latter pathologic changes, although some studies indicate a few complications that need to be considered in the long-term administration of the hormone. As such, this review will illustrate the wide-ranging neuroprotective properties of acylated ghrelin and critically evaluate the hormone's therapeutic benefits for the treatment of AD and PD.

scholarly journals Gastrointestinal Biopsies for the Diagnosis of Alpha-Synuclein Pathology in Parkinson’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Maria Graciela Cersosimo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Alpha Synuclein ◽  
Biopsy Material ◽  
Autopsy Examination ◽  
Colon And Rectum ◽  
Rostrocaudal Gradient

The diagnosis of Parkinson’s disease (PD) relies on clinical features whereas pathological confirmation is only possible with autopsy examination. The neuropathological hallmarks of PD are neuronal loss and the presence of inclusions termed Lewy bodies/neurites in affected regions. A major component of these inclusions is phosphorylated alpha-synuclein (α-SYN) protein. There is evidence thatα-SYN pathology is widely distributed outside the central nervous system in patients with PD. The gastrointestinal tract is importantly affected byα-SYN containing inclusions and typically there is a rostrocaudal gradient for the distribution of the pathology. The highest amounts of Lewy bodies/neurites are found at the submandibular gland together with the lower esophagus and the lowest amounts are found in the rectum. Autopsy findings prompted research aimed at achieving in vivo pathological diagnosis of PD by demonstrating the presence ofα-SYN pathology in biopsy material of these peripheral accessible tissues. So far, biopsy studies of the gut have demonstrated the presence ofα-SYN pathology in the salivary glands, stomach, duodenum, colon, and rectum. Further research is necessary in order to determine which are the most sensitive targets for in vivoα-SYN pathology detection and the safest techniques for these approaches in patients with PD.

scholarly journals DNAJB6 Suppresses Alpha-synuclein Induced Pathology in an Animal Model of Parkinson’s Disease

2020 ◽  
Author(s):  
Sertan Arkan ◽  
Mårten Ljungberg ◽  
Deniz Kirik ◽  
Christian Hansen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Cell Death ◽  
Alpha Synuclein ◽  
Cellular Level ◽  
Substantia Nigra Pars Compacta ◽  
Motor Deficits ◽  
Dopaminergic Cell ◽  
Knock Out

Abstract Background: α-synuclein (α-syn) aggregation can lead to degeneration of dopaminergic neurons in the substantia nigra pars compacta ( SNpc ) as invariably observed in patients with Parkinson’s Disease (PD). The co-chaperone DNAJB6 has previously been found to be expressed at higher levels in PD patients than in control subjects and was also found in Lewy bodies. Our previous experiments showed that knock out of DNAJB6 induced α-syn aggregation in cellular level. However, effects of overexpression of DNAJB6 against α-syn aggregation remains to be investigated. Methods: we used to α-syn CFP/YFP HEK293 FRET cell line to investigate the effects of overexpression of DNAJB6 in cellular level. α-syn aggregation was induced by transfection α-syn preformed fibrils (PPF), then was measured FRET analysis. We proceeded to investigate if DNAJB6b can impair α-syn aggregation and toxicity in an animal model and used adeno associated vira (AAV6) designed to overexpress of human wt α-syn, GFP-DNAJB6 or GFP in rats. These vectors were injected into the SNpc of the rats, unilaterally. Rats injected with vira to express α-syn along with GFP in the SNpc where compared to rats expressing α-syn and GFP-DNAJB6. We evaluated motor functions, dopaminergic cell death, phosphorylated α-syn in SNpc and axonal degeneration in striatum. Results : We show that DNAJB6 prevent α-syn aggregation induced by α-syn PFF’s, in a cell culture model. Also, we observed α-syn overexpression caused dopaminergic cell death and that this was strongly reduced by co-expression of DNAJB6b. In addition, the lesion caused by α-syn overexpression resulted in behavior deficits, which increased over time as seen in stepping test, which was rescued by co-expression of DNAJB6b. Moreover, we observed an increase in serine 129 (S129) phosphorylated α-syn in SNpc of rats overexpressing α-syn, that was lowered by DNAJB6 co-expression. Conclusion : We here demonstrate for the first time that DNAJB6 is a strong suppressor of α-syn aggregation in cells and in animals and that this results in a suppression of dopaminergic cell death and PD related motor deficits in an animal model of PD. Keywords: Protein homeostasis, Parkinson`s Disease, Alpha-synuclein, Adeno Associated Virus, DNAJB6, Heat Shock Protein 70

scholarly journals Pesticides and Parkinson’s disease: A potential hazard in agricultural communities

2017 ◽  
Vol 5 (20) ◽  
pp. 60
Author(s):  
Smathorn Thakolwiboon ◽  
Parunyou Julayanont ◽  
Doungporn Ruthirago
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Synergistic Effects ◽  
Neuronal Loss ◽  
Ubiquitin Proteasome System ◽  
Alpha Synuclein ◽  
Current Evidence ◽  
Potential Hazard ◽  
Dopaminergic Neuronal Loss

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder. Its pathogenesis isrelated to both genetic and environmental factors. Current evidence suggests that pesticideexposure is one of the risk factors of PD. In this review, we summarize four molecularmechanisms of pesticide-induced PD with supportive evidences from both laboratory andepidemiological studies. Rotenone is the first pesticide reported to be associated with PD byinhibiting complex I of mitochondrial electron transport chain. Paraquat, a commonly-usedherbicide in some countries, is an oxidative stressor causing dopaminergic neuronal loss whichcontributes to the pathogenesis of PD. The ubiquitin-proteasome system (UPS) and aldehydedehydrogenase (ALDH) inhibitors cause unwanted proteins (especially alpha-synuclein) and3,4-dihydroxyphenylacetaldehyde (DOPAL) accumulation leading to dopaminergic neuronalapoptosis. In addition, exposure to different pesticides affecting different mechanisms mayhave synergistic effects in increasing risk of PD. Protective glove use, the amount of fat intake,and neuroprotective agents are reported to have disease modification effects for pesticideassociatedPD.

scholarly journals Analysis of the Relationship between Type II Diabetes Mellitus and Parkinson’s Disease: A Systematic Review

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Fauze Camargo Maluf ◽  
David Feder ◽  
Alzira Alves de Siqueira Carvalho
Keyword(s):  
Diabetes Mellitus ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Type Ii Diabetes ◽  
Type Ii Diabetes Mellitus ◽  
Alpha Synuclein ◽  
Peroxisome Proliferator ◽  
Type Ii ◽  
Peroxisome Proliferator Activated Receptor

In the early sixties, a discussion started regarding the association between Parkinson’s disease (PD) and type II diabetes mellitus (T2DM). Today, this potential relationship is still a matter of debate. This review aims to analyze both diseases concerning causal relationships and treatments. A total of 104 articles were found, and studies on animal and “in vitro” models showed that T2DM causes neurological alterations that may be associated with PD, such as deregulation of the dopaminergic system, a decrease in the expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), an increase in the expression of phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes 15 (PED/PEA-15), and neuroinflammation, as well as acceleration of the formation of alpha-synuclein amyloid fibrils. In addition, clinical studies described that Parkinson’s symptoms were notably worse after the onset of T2DM, and seven deregulated genes were identified in the DNA of T2DM and PD patients. Regarding treatment, the action of antidiabetic drugs, especially incretin mimetic agents, seems to confer certain degree of neuroprotection to PD patients. In conclusion, the available evidence on the interaction between T2DM and PD justifies more robust clinical trials exploring this interaction especially the clinical management of patients with both conditions.

scholarly journals The Impact of SNCA Variations and Its Product Alpha-Synuclein on Non-Motor Features of Parkinson’s Disease

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 804
Author(s):  
Luca Magistrelli ◽  
Elena Contaldi ◽  
Cristoforo Comi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Decline ◽  
Neuronal Degeneration ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Main Component ◽  
The Impact

Parkinson’s disease (PD) is a common and progressive neurodegenerative disease, caused by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which is clinically characterized by a constellation of motor and non-motor manifestations. The latter include hyposmia, constipation, depression, pain and, in later stages, cognitive decline and dysautonomia. The main pathological features of PD are neuronal loss and consequent accumulation of Lewy bodies (LB) in the surviving neurons. Alpha-synuclein (α-syn) is the main component of LB, and α-syn aggregation and accumulation perpetuate neuronal degeneration. Mutations in the α-syn gene (SNCA) were the first genetic cause of PD to be identified. Generally, patients carrying SNCA mutations present early-onset parkinsonism with severe and early non-motor symptoms, including cognitive decline. Several SNCA polymorphisms were also identified, and some of them showed association with non-motor manifestations. The functional role of these polymorphisms is only partially understood. In this review we explore the contribution of SNCA and its product, α-syn, in predisposing to the non-motor manifestations of PD.

scholarly journals A Summary of Phenotypes Observed in the In Vivo Rodent Alpha-Synuclein Preformed Fibril Model

2021 ◽  
pp. 1-13
Author(s):  
Nicole K. Polinski
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Study Design ◽  
Alpha Synuclein ◽  
Therapeutic Strategies ◽  
Rodent Model ◽  
In Vivo Model ◽  
Nigrostriatal Degeneration ◽  
The Brain

The use of wildtype recombinant alpha-synuclein preformed fibrils (aSyn PFFs) to induce endogenous alpha-synuclein to form pathological phosphorylation and trigger neurodegeneration is a popular model for studying Parkinson’s disease (PD) biology and testing therapeutic strategies. The strengths of this model lie in its ability torecapitulatethe phosphorylation/aggregationof aSyn and nigrostriatal degeneration seen in PD, as well as its suitability for studying the progressive nature of PD and the spread of aSyn pathology. Although the model is commonly used and has been adopted by many labs, variability in observed phenotypes exists. Here we provide summaries of the study design and reported phenotypes frompublished reports characterizing the aSyn PFF in vivo model in rodents following injection into the brain, gut, muscle, vein, peritoneum, and eye. These summariesare designed to facilitate an introduction to the use of aSyn PFFs to generate a rodent model of PD—highlighting phenotypes observed in papers that set out to thoroughly characterize the model.This information will hopefully improve the understanding of this model and clarify when the aSyn PFF model may be an appropriate choice for one’s research.

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