Infection and Risk of Parkinson’s Disease

Parkinson’s disease (PD) is thought to be caused by a combination of genetic and environmental factors. Bacterial or viral infection has been proposed as a potential risk factor, and there is supporting although not entirely consistent epidemiologic and basic science evidence to support its role. Encephalitis caused by influenza has included parkinsonian features. Epidemiological evidence is most compelling for an association between PD and hepatitis C virus. Infection with Helicobacter pylori may be associated not only with PD risk but also response to levodopa. Rapidly evolving knowledge regarding the role of the microbiome also suggests a role of resident bacteria in PD risk. Biological plausibility for the role for infectious agents is supported by the known neurotropic effects of specific viruses, particular vulnerability of the substantia nigra and even the promotion of aggregation of alpha-synuclein. A common feature of implicated viruses appears to be production of high levels of cytokines and chemokines that can cross the blood-brain barrier leading to microglial activation and inflammation and ultimately neuronal cell death. Based on multiple avenues of evidence it appears likely that specific bacterial and particularly viral infections may increase vulnerability to PD. The implications of this for PD prevention requires attention and may be most relevant once preventive treatments for at-risk populations are developed.

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Alpha-synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome

Biology Open ◽

10.1242/bio.054338 ◽

2020 ◽

Vol 9 (10) ◽

pp. bio054338

Author(s):

Anila Iqbal ◽

Marta Baldrighi ◽

Jennifer N. Murdoch ◽

Angeleen Fleming ◽

Christopher J. Wilkinson

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Intracellular Transport ◽

Neuronal Cell Death ◽

Lewy Bodies ◽

Neuronal Cell ◽

Cell Types ◽

Alpha Synuclein ◽

Microtubule Network ◽

Main Component

ABSTRACTProtein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the accumulation of α-synuclein, the main component of Lewy bodies found in Parkinson's disease. Aggresomes are closely-related, cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organise the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to functional deficits and neuronal cell death in Parkinson's disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.

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Acrolein-mediated neuronal cell death and alpha-synuclein aggregation: Implications for Parkinson's disease

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2018.01.006 ◽

2018 ◽

Vol 88 ◽

pp. 70-82 ◽

Cited By ~ 13

Author(s):

Abeje Ambaw ◽

Lingxing Zheng ◽

Mitali A. Tambe ◽

Katherine E. Strathearn ◽

Glen Acosta ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Alpha Synuclein ◽

Alpha Synuclein Aggregation

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Alpha synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome

10.1101/2019.12.20.884643 ◽

2019 ◽

Author(s):

Anila Iqbal ◽

Marta Baldrighi ◽

Jennifer N. Murdoch ◽

Angeleen Fleming ◽

Christopher J. Wilkinson

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Intracellular Transport ◽

Neuronal Cell Death ◽

Lewy Bodies ◽

Neuronal Cell ◽

Cell Types ◽

Alpha Synuclein ◽

Microtubule Network

AbstractProtein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the Lewy bodies found in Parkinson’s disease. Aggresomes are closely-related cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede the organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organize the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since dopaminergic neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to loss of dopaminergic function and neuronal cell death in Parkinson’s disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.

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Parkinson’s Disease-Related Genes and Lipid Alteration

International Journal of Molecular Sciences ◽

10.3390/ijms22147630 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7630

Author(s):

Milena Fais ◽

Antonio Dore ◽

Manuela Galioto ◽

Grazia Galleri ◽

Claudia Crosio ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Clinical Manifestations ◽

Alpha Synuclein ◽

Experimental Models ◽

Protein Clearance ◽

Genetic And Environmental Factors

Parkinson’s disease (PD) is a complex and progressive neurodegenerative disorder with a prevalence of approximately 0.5–1% among those aged 65–70 years. Although most of its clinical manifestations are due to a loss of dopaminergic neurons, the PD etiology is largely unknown. PD is caused by a combination of genetic and environmental factors, and the exact interplay between genes and the environment is still debated. Several biological processes have been implicated in PD, including mitochondrial or lysosomal dysfunctions, alteration in protein clearance, and neuroinflammation, but a common molecular mechanism connecting the different cellular alterations remains incompletely understood. Accumulating evidence underlines a significant role of lipids in the pathological pathways leading to PD. Beside the well-described lipid alteration in idiopathic PD, this review summarizes the several lipid alterations observed in experimental models expressing PD-related genes and suggests a possible scenario in relationship to the molecular mechanisms of neuronal toxicity. PD could be considered a lipid-induced proteinopathy, where alteration in lipid composition or metabolism could induce protein alteration—for instance, alpha-synuclein accumulation—and finally neuronal death.

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P.5.c.002 The role of sphingosine kinase-1 in alpha-synuclein secretion and neuronal cell death mechanism in an experimental model of Parkinson's disease

European Neuropsychopharmacology ◽

10.1016/s0924-977x(14)71032-6 ◽

2014 ◽

Vol 24 ◽

pp. S642

Author(s):

J. Pyszko ◽

J.B. Strosznajder

Keyword(s):

Parkinson’S Disease ◽

Cell Death ◽

Experimental Model ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Sphingosine Kinase ◽

Alpha Synuclein ◽

Sphingosine Kinase 1 ◽

Cell Death Mechanism

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Faculty Opinions recommendation of The role of ubiquitin linkages on alpha-synuclein induced-toxicity in a Drosophila model of Parkinson's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13371031.14741147 ◽

2011 ◽

Author(s):

Keith Wilkinson

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Alpha Synuclein ◽

Drosophila Model

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Cytokinin Plant Hormones Have Neuroprotective Activity in In Vitro Models of Parkinson’s Disease

Molecules ◽

10.3390/molecules26020361 ◽

2021 ◽

Vol 26 (2) ◽

pp. 361

Author(s):

Gabriel Gonzalez ◽

Jiří Grúz ◽

Cosimo Walter D’Acunto ◽

Petr Kaňovský ◽

Miroslav Strnad

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Neuronal Cell Death ◽

Disease Model ◽

Neuronal Cell ◽

Zeatin Riboside ◽

Neuroprotective Activity ◽

Protective Activity

Cytokinins are adenine-based phytohormones that regulate key processes in plants, such as cell division and differentiation, root and shoot growth, apical dominance, branching, and seed germination. In preliminary studies, they have also shown protective activities against human neurodegenerative diseases. To extend knowledge of the protection (protective activity) they offer, we investigated activities of natural cytokinins against salsolinol (SAL)-induced toxicity (a Parkinson’s disease model) and glutamate (Glu)-induced death of neuron-like dopaminergic SH-SY5Y cells. We found that kinetin-3-glucoside, cis-zeatin riboside, and N6-isopentenyladenosine were active in the SAL-induced PD model. In addition, trans-, cis-zeatin, and kinetin along with the iron chelator deferoxamine (DFO) and the necroptosis inhibitor necrostatin 1 (NEC-1) significantly reduced cell death rates in the Glu-induced model. Lactate dehydrogenase assays revealed that the cytokinins provided lower neuroprotective activity than DFO and NEC-1. Moreover, they reduced apoptotic caspase-3/7 activities less strongly than DFO. However, the cytokinins had very similar effects to DFO and NEC-1 on superoxide radical production. Overall, they showed protective activity in the SAL-induced model of parkinsonian neuronal cell death and Glu-induced model of oxidative damage mainly by reduction of oxidative stress.

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Potential role of protein stabilizers in amelioration of Parkinson's disease and associated effects in transgenic Caenorhabditis elegans model expressing alpha-synuclein

RSC Advances ◽

10.1039/c5ra13546j ◽

2015 ◽

Vol 5 (95) ◽

pp. 77706-77715 ◽

Cited By ~ 4

Author(s):

Supinder Kaur ◽

Aamir Nazir

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Caenorhabditis Elegans ◽

Potential Role ◽

Alpha Synuclein ◽

C Elegans

Studies employing transgenicC. elegansmodel show that trehalose, a protein stabilizer, alleviates manifestations associated with Parkinson's diseaseviaits inherent activity and through induction of autophagic machinery.

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Subcellular orchestration of alpha-synuclein variants in Parkinson’s disease brains revealed by 3D multicolor STED microscopy

10.1101/470476 ◽

2018 ◽

Cited By ~ 7

Author(s):

Tim E. Moors ◽

Christina A. Maat ◽

Daniel Niedieker ◽

Daniel Mona ◽

Dennis Petersen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lewy Bodies ◽

Distribution Patterns ◽

Alpha Synuclein ◽

Label Free ◽

Post Translational Modifications ◽

Sted Microscopy ◽

C Terminus

AbstractPost-translational modifications of alpha-synuclein (aSyn), particularly phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinson’s disease (PD) pathology. To gain more insight in the relevance of Ser129-p and CTT aSyn under physiological and pathological conditions, we investigated their subcellular distribution patterns in normal aged and PD brains using highly-selective antibodies in combination with 3D multicolor STED microscopy. We show that CTT aSyn localizes in mitochondria in PD patients and controls, whereas the organization of Ser129-p in a cytoplasmic network is strongly associated with pathology. Nigral Lewy bodies show an onion skin-like architecture, with a structured framework of Ser129-p aSyn and neurofilaments encapsulating CTT aSyn in their core, which displayed high content of proteins and lipids by label-free CARS microscopy. The subcellular phenotypes of antibody-labeled pathology identified in this study provide evidence for a crucial role of Ser129-p aSyn in Lewy body formation.

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