scholarly journals Parkinson’s Disease Dementia: Synergistic Effects of Alpha-Synuclein, Tau, Beta-Amyloid, and Iron

2021 ◽  
Vol 13 ◽  
Author(s):  
Jiajun Han ◽  
Yaohua Fan ◽  
Peipei Wu ◽  
Zifeng Huang ◽  
Xinrong Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Glycogen Synthase ◽  
Synergistic Effects ◽  
Beta Amyloid ◽  
Alpha Synuclein ◽  
Protein Accumulation ◽  
Vicious Cycle ◽  
Parkinson’S Disease Dementia ◽  
Post Translational Modification

Parkinson’s disease dementia (PDD) is a common complication of Parkinson’s disease that seriously affects patients’ health and quality of life. At present, the process and pathological mechanisms of PDD remain controversial, which hinders the development of treatments. An increasing number of clinical studies have shown that alpha-synuclein (α-syn), tau, beta-amyloid (Aβ), and iron are closely associated with PDD severity. Thus, we inferred the vicious cycle that causes oxidative stress (OS), due to the synergistic effects of α-syn, tau, Aβ, and, iron, and which plays a pivotal role in the mechanism underlying PDD. First, iron-mediated reactive oxygen species (ROS) production can lead to neuronal protein accumulation (e.g., α-syn andAβ) and cytotoxicity. In addition, regulation of post-translational modification of α-syn by iron affects the aggregation or oligomer formation of α-syn. Iron promotes tau aggregation and neurofibrillary tangles (NFTs) formation. High levels of iron, α-syn, Aβ, tau, and NFTs can cause severe OS and neuroinflammation, which lead to cell death. Then, the increasing formation of α-syn, Aβ, and NFTs further increase iron levels, which promotes the spread of α-syn and Aβ in the central and peripheral nervous systems. Finally, iron-induced neurotoxicity promotes the activation of glycogen synthase kinase 3β (GSK3β) related pathways in the synaptic terminals, which in turn play an important role in the pathological synergistic effects of α-syn, tau and Aβ. Thus, as the central factor regulating this vicious cycle, GSK3β is a potential target for the prevention and treatment of PDD; this is worthy of future study.

scholarly journals Combined Analysis of CSF Tau, Aβ42, Aβ1–42% and Aβ1–40ox% in Alzheimer's Disease, Dementia with Lewy Bodies and Parkinson's Disease Dementia

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Mirko Bibl ◽  
Hermann Esselmann ◽  
Piotr Lewczuk ◽  
Claudia Trenkwalder ◽  
Markus Otto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Diagnostic Value ◽  
Alpha Synuclein ◽  
Parkinson’S Disease Dementia ◽  
Sds Page

We studied the diagnostic value of CSF Aβ42/tau versus low Aβ1–42% and high Aβ1–40ox% levels for differential diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), respectively. CSF of 45 patients with AD, 15 with DLB, 21 with Parkinson's disease dementia (PDD), and 40 nondemented disease controls (NDC) was analyzed by Aβ-SDS-PAGE/immunoblot and ELISAs (Aβ42 and tau). Aβ42/tau lacked specificity in discriminating AD from DLB and PDD. Best discriminating biomarkers were Aβ1–42% and Aβ1–40ox% for AD and DLB, respectively. AD and DLB could be differentiated by both Aβ1–42% and Aβ1–40ox% with an accuracy of 80% at minimum. Thus, we consider Aβ1–42% and Aβ1–40ox% to be useful biomarkers for AD and DLB, respectively. We propose further studies on the integration of Aβ1–42% and Aβ1–40ox% into conventional assay formats. Moreover, future studies should investigate the combination of Aβ1–40ox% and CSF alpha-synuclein for the diagnosis of DLB.

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 Beta-Amyloid, Phospho-Tau and Alpha-Synuclein Deposits Similar to Those in the Brain Are Not Identified in the Eyes of Alzheimer's and Parkinson's Disease Patients

2013 ◽  
Vol 24 (1) ◽  
pp. 25-32 ◽  
Author(s):  
Cheng-Ying Ho ◽  
Juan C. Troncoso ◽  
David Knox ◽  
Walter Stark ◽  
Charles G. Eberhart
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Beta Amyloid ◽  
Alpha Synuclein ◽  
The Brain

scholarly journals Parkinson's disease dementia and dementia with Lewy bodies – epidemiology, risk factors and biomarkers

2012 ◽  
Vol 22 (2) ◽  
Author(s):  
Eirik Auning ◽  
Arvid Rongve ◽  
Dag Aarsland
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Dementia With Lewy Bodies ◽  
Strong Predictor ◽  
Lewy Bodies ◽  
Epidemiological Studies ◽  
Alpha Synuclein ◽  
Parkinson’S Disease Dementia ◽  
Autonomic Disturbances

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are common and debilitating dementia syndromes accompanied by Parkinsonism and a range of other psychiatric, sleep and autonomic disturbances. Disease mechanisms are unknown, but aggregated Lewy bodies containing alpha-synuclein are believed to play a central role in the pathogenesis. Point-prevalence of dementia in Parkinson's disease (PD) is approximately 30%, and the majority develop dementia as the disease progresses. Recent studies suggest that 25-30% of non-demented PD patients have mild cognitive impairment (MCI), and 15-20% already have it at the time of the diagnosis. PD-MCI is a strong predictor of PDD. There are few welldesigned epidemiological studies of DLB, but available evidence suggests that 15-20% of the total dementia population have DLB. Predicting future cognitive impairment is a priority, but the pre-dementia stage of DLB is essentially unexplored. Promising biomarkers are being researched, but, given the complexity of this disease, a multimodal approach is more likely to permit diagnostic precision in the future.

scholarly journals Alpha-Synuclein is a Target of Fic-mediated Adenylylation/AMPylation: Implications for Parkinson’s Disease

2019 ◽  
Author(s):  
Anwesha Sanyal ◽  
Sayan Dutta ◽  
Aswathy Chandran ◽  
Antonius Koller ◽  
Ali Camara ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Er Stress ◽  
Cell Fate ◽  
Alpha Synuclein ◽  
Misfolded Proteins ◽  
List Type ◽  
Post Translational Modification ◽  
Presynaptic Protein

ABSTRACTDuring disease, cells experience various stresses that manifest as an accumulation of misfolded proteins and eventually lead to cell death. To combat this stress, cells activate a pathway called UPR (Unfolded Protein Response) that functions to maintain ER (endoplasmic reticulum) homeostasis and determines cell fate. We recently reported a hitherto unknown mechanism of regulating ER stress via a novel post-translational modification (PTM) called Fic-mediated Adenylylation/AMPylation. Specifically, we showed that the human Fic (filamentation induced by cAMP) protein, HYPE/FicD, catalyzes the addition of an AMP (adenosine monophosphate) to the ER chaperone, BiP, to alter the cell’s UPR-mediated response to misfolded proteins. Here, we report that we have now identified a second target for HYPE - alpha-Synuclein (αSyn), a presynaptic protein involved in Parkinson’s disease (PD). Aggregated αSyn has been shown to induce ER stress and elicit neurotoxicity in PD models. We show that HYPE adenylylates αSyn and reduces phenotypes associated with αSyn aggregation in vitro, suggesting a possible mechanism by which cells cope with αSyn toxicity.HIGHLIGHTSAggregated forms of the presynaptic protein αSyn cause neurotoxicity and induce ER stress in cellular and animal models of Parkinson’s disease.We have identified αSyn as a novel target for the human Fic protein, HYPE, a key regulator of ER homeostasis.HYPE adenylylates αSyn and reduces the aggregation of recombinant αSynFic-mediated adenylylation/AMPylation is a possible mechanism by which cells cope with αSyn toxicity.Graphic Abstract

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