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

Biology Open ◽  
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.

scholarly journals Alpha synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome

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.

scholarly journals Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD

2011 ◽  
Vol 2011 ◽  
pp. 1-20 ◽  
Author(s):  
A. R. Esteves ◽  
D. M. Arduíno ◽  
D. F. F. Silva ◽  
C. R. Oliveira ◽  
S. M. Cardoso
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Neuronal Cell ◽  
Alpha Synuclein ◽  
Vital Role ◽  
Microtubule Network ◽  
The Road ◽  
Species Production ◽  
Alpha Synuclein Aggregation

While the etiology of Parkinson's disease remains largely elusive, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in Parkinson's disease. Mitochondria are remarkably primed to play a vital role in neuronal cell survival since they are key regulators of energy metabolism (as ATP producers), of intracellular calcium homeostasis, of NAD+/NADH ratio, and of endogenous reactive oxygen species production and programmed cell death. In this paper, we focus on mitochondrial dysfunction-mediated alpha-synuclein aggregation. We highlight some of the findings that provide proof of evidence for a mitochondrial metabolism control in Parkinson's disease, namely, mitochondrial regulation of microtubule-dependent cellular traffic and autophagic lysosomal pathway. The knowledge that microtubule alterations may lead to autophagic deficiency and may compromise the cellular degradation mechanisms that culminate in the progressive accumulation of aberrant protein aggregates shields new insights to the way we address Parkinson's disease. In line with this knowledge, an innovative window for new therapeutic strategies aimed to restore microtubule network may be unlocked.

scholarly journals Diversity in the Regulation of Autophagy and Mitophagy: Lessons from Parkinson's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Charleen T. Chu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cell Types ◽  
Mitochondrial Targeting ◽  
Neuronal Function ◽  
Inner Mitochondrial Membrane ◽  
Canonical Pathways

Selective mitochondrial degradation through autophagy (mitophagy) has emerged as an important homeostatic mechanism in a variety of organisms and contexts. Complete clearance of mitochondria can be observed during normal maturation of certain mammalian cell types, and during certain forms of neuronal cell death. In recent years, autophagy dysregulation has been implicated in toxin-injured dopaminergic neurons as well as in major genetic models of Parkinson's disease (PD), includingα-synuclein, leucine-rich repeat kinase 2 (LRRK2), parkin, PTEN-induced kinase 1 (PINK1), and DJ-1. Indeed, PINK1-parkin interactions may form the basis of a mechanism by which dissipation of the inner mitochondrial membrane potential can trigger selective mitochondrial targeting for autophagy. Multiple signals are likely to exist, however, depending upon the trigger for mitophagy. Similarly, the regulation of basal or injury-induced autophagy does not always follow canonical pathways described for nutrient deprivation. Implications of this regulatory diversity are discussed in the context of neuronal function and survival. Further studies are needed to address whether alterations in autophagy regulation play a directly injurious role in PD pathogenesis, or if the observed changes reflect impaired, appropriate, or excessive autophagic responses to other forms of cellular injury.

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

2018 ◽  
Vol 88 ◽  
pp. 70-82 ◽  
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

scholarly journals Alpha-Synuclein in Parkinson’s Disease: From Pathogenetic Dysfunction to Potential Clinical Application

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Lingjia Xu ◽  
Jiali Pu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Current Knowledge ◽  
Point Mutations ◽  
Lewy Bodies ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Lewy Neurites

Parkinson’s disease is a neurodegenerative disease/synucleinopathy that develops slowly; however, there is no efficient method of early diagnosis, nor is there a cure. Progressive dopaminergic neuronal cell loss in the substantia nigra pars compacta and widespread aggregation of theα-synuclein protein (encoded by theSNCAgene) in the form of Lewy bodies and Lewy neurites are the neuropathological hallmarks of Parkinson’s disease. TheSNCAgene has undergone gene duplications, triplications, and point mutations. However, the specific mechanism ofα-synuclein in Parkinson’s disease remains obscure. Recent research showed that variousα-synuclein oligomers, pathological aggregation, and propagation appear to be harmful in certain areas in Parkinson’s disease patients. This review summarizes our current knowledge of the pathogenetic dysfunction ofα-synuclein associated with Parkinson’s disease and highlights current approaches that seek to develop this protein as a possible diagnostic biomarker and therapeutic target.

scholarly journals Alpha-Synuclein in Alcohol Use Disorder, Connections with Parkinson’s Disease and Potential Therapeutic Role of 5’ Untranslated Region-Directed Small Molecules

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1465
Author(s):  
Catherine M. Cahill ◽  
Rozaleen Aleyadeh ◽  
Jin Gao ◽  
Changning Wang ◽  
Jack T. Rogers
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alcohol Use ◽  
Small Molecules ◽  
Untranslated Region ◽  
Alcohol Use Disorder ◽  
Lewy Bodies ◽  
Neuronal Cell ◽  
Alpha Synuclein ◽  
Divalent Metal Ions

Alpha-synuclein (α-Syn) is a 140-amino acid (aa) protein encoded by the Synuclein alpha SNCA gene. It is the synaptic protein associated with Parkinson’s disease (PD) and is the most highly expressed protein in the Lewy bodies associated with PD and other alpha synucleopathies, including Lewy body dementia (LBD) and multiple system atrophy (MSA). Iron deposits are present in the core of Lewy bodies, and there are reports suggesting that divalent metal ions including Cu2+ and Fe2+ enhance the aggregation of α-Syn. Differential expression of α-Syn is associated with alcohol use disorder (AUD), and specific genetic variants contribute to the risk for alcoholism, including alcohol craving. Spliced variants of α-Syn, leading to the expression of several shorter forms which are more prone to aggregation, are associated with both PD and AUD, and common transcript variants may be able to predict at-risk populations for some movement disorders or subtypes of PD, including secondary Parkinsonism. Both PD and AUD are associated with liver and brain iron dyshomeostasis. Research over the past decade has shown that α-Syn has iron import functions with an ability to oxidize the Fe3+ form of iron to Fe2+ to facilitate its entry into cells. Our prior research has identified an iron-responsive element (IRE) in the 5’ untranslated region (5’UTR) of α-Syn mRNA, and we have used the α-Syn 5’UTR to screen for small molecules that modulate its expression in the H4 neuronal cell line. These screens have led us to identify several interesting small molecules capable of both decreasing and increasing α-Syn expression and that may have the potential, together with the recently described mesenchymal stem cell therapies, to normalize α-Syn expression in different regions of the alcoholic and PD brain.

scholarly journals Infection and Risk of Parkinson’s Disease

2020 ◽  
pp. 1-13
Author(s):  
Richard J. Smeyne ◽  
Alastair J Noyce ◽  
Matthew Byrne ◽  
Rodolfo Savica ◽  
Connie Marras
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Viral Infections ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Alpha Synuclein ◽  
Cytokines And Chemokines ◽  
Genetic And Environmental Factors ◽  
Neurotropic Effects

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.

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

Molecules ◽  
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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