scholarly journals Is Parkinson’s Disease Truly a Prion-Like Disorder? An Appraisal of Current Evidence

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Aneesha Chauhan ◽  
Alexander F. Jeans
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Short Review ◽  
Current Evidence ◽  
Symptomatic Therapy ◽  
Therapeutic Implications ◽  
A Cell ◽  
Direct Targeting ◽  
Main Component

Parkinson’s disease (PD) is the world’s second most common neurodegenerative disease and most common movement disorder. Characterised by a loss of dopaminergic neurons and the development of intraneuronal inclusions known as Lewy bodies, it has classically been thought of as a cell-autonomous disease. However, in 2008, two groups reported the startling observation of Lewy bodies within embryonic neuronal grafts transplanted into PD patients little more than a decade previously, suggesting that PD pathology can be propagated to neighbouring cells and calling basic assumptions of our understanding of the disease into question. Subsequent research has largely served to confirm this interpretation, pointing towards a prion-like intercellular transfer of misfoldedα-synuclein, the main component of Lewy bodies, as central to PD. This shift in thinking offers a revolutionary approach to PD treatment, potentially enabling a transition from purely symptomatic therapy to direct targeting of the pathology that drives disease progression. In this short review, we appraise current experimental support for PD as a prion-like disease, whilst highlighting areas of controversy or inconsistency which must be resolved. We also offer a brief discussion of the therapeutic implications of these discoveries.

scholarly journals Treating Parkinson’s Disease with Antibodies: Previous Studies and Future Directions

2020 ◽  
pp. 1-22
Author(s):  
Anne-Marie Castonguay ◽  
Claude Gravel ◽  
Martin Lévesque
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Passive Immunization ◽  
Lewy Bodies ◽  
Gene Mutations ◽  
Alpha Synuclein ◽  
Multiple Sources ◽  
Immunization Strategies ◽  
A Cell

Parkinson’s disease is a neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons in the substantia nigra. Degenerating neurons contain abnormal aggregates called Lewy bodies, that are predominantly composed of the misfolded and/or mutated alpha-synuclein protein. Post-translational modifications, cellular stress, inflammation and gene mutations are thought to trigger its pathological misfolding and aggregation. With alpha-synuclein pathology being strongly associated with dopaminergic neuronal toxicity, strategies aimed to reduce its burden are expected to be beneficial in slowing disease progression. Moreover, multiple sources of evidence suggest a cell-to-cell transmission of pathological alpha-synuclein in a prion-like manner. Therefore, antibodies targeting extra- or intracellular alpha-synuclein could be efficient in limiting the aggregation and transmission. Several active and passive immunization strategies have been explored to target alpha-synuclein. Here, we summarize immunotherapeutic approaches that were tested in pre-clinical or clinical studies in the last two decades in an attempt to treat Parkinson’s disease.

scholarly journals Tau in the Pathophysiology of Parkinson’s Disease

2021 ◽  
Author(s):  
Lina Pan ◽  
Lanxia Meng ◽  
Mingyang He ◽  
Zhentao Zhang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genome Wide Association Study ◽  
Lewy Bodies ◽  
Current Evidence ◽  
Gene Encoding ◽  
Passive Element ◽  
Genome Wide ◽  
A Genome ◽  
And Function

AbstractThe pathological hallmarks of Parkinson's disease (PD) are the progressive loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (LBs) in remaining neurons. LBs primarily consist of aggregated α-Synuclein (α-Syn). However, accumulating evidence suggests that Tau, which is associated with tauopathies such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and argyrophilic grain disease, is also involved in the pathophysiology of PD. A genome-wide association study (GWAS) identified MAPT, the gene encoding the Tau protein, as a risk gene for PD. Autopsy of PD patients also revealed the colocalization of Tau and α-Syn in LBs. Experimental evidence has shown that Tau interacts with α-Syn and influences the pathology of α-Syn in PD. In this review, we discuss the structure and function of Tau and provide a summary of the current evidence supporting Tau’s involvement as either an active or passive element in the pathophysiology of PD, which may provide novel targets for the early diagnosis and treatment of PD.

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 Clinical Trials in Parkinson's Disease Dementia and Dementia with Lewy Bodies

2007 ◽  
Vol 34 (S1) ◽  
pp. S109-S117 ◽  
Author(s):  
Richard Camicioli ◽  
Serge Gauthier
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Dementia With Lewy Bodies ◽  
Motor Impairment ◽  
Lewy Bodies ◽  
Behavioral Impairment ◽  
Consensus Definition ◽  
Therapeutic Implications

Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are pathological overlapping and important causes of dementia for which clinical trials are in their infancy. Cholinesterase inhibitors may be of benefit in DLB and PDD, as suggested by placebo-controlled clinical trials of rivastigmine and donepezil. The anti-psychotic agent clozapine has been of benefit in PD and PDD, but other agents, such as quetiapine, require adequate assessment. Barriers to trials include pathological overlap that can lead to inaccuracies in clinical diagnosis, unavailability of a consensus definition for PDD, unanswered questions regarding natural history and the paucity of validated outcome measures. Motor impairment must be considered in patients with PDD and DLB; conversely, cognitive impairment should be assessed in trials targeting motor impairment in advanced PD. Potential targets for treatment include onset of dementia, cognitive impairment, behavioral impairment, functional decline, falls, nursing home placement, mortality, quality of life and economic impact. Biomarkers including neuroimaging and cerebrospinal fluid markers are not currently established. At present PDD and DLB are distinct entities by definition. Future studies, including clinical trials and biomarker studies, will help to further define the clinical and therapeutic implications of this distinction.

scholarly journals C-Abl Inhibition; A Novel Therapeutic Target for Parkinson's Disease

2018 ◽  
Vol 17 (1) ◽  
pp. 14-21 ◽  
Author(s):  
Abdelrahman Ibrahim Abushouk ◽  
Ahmed Negida ◽  
Rasha Abdelsalam Elshenawy ◽  
Hossam Zein ◽  
Ali M. Hammad ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Targets ◽  
Experimental Studies ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Current Evidence ◽  
Future Research ◽  
Neuroprotective Effects ◽  
Human Trial

Parkinson's disease (PD) is the most prevalent movement disorder in the world. The major pathological hallmarks of PD are death of dopaminergic neurons and the formation of Lewy bodies. At the moment, there is no cure for PD; current treatments are symptomatic. Investigators are searching for neuroprotective agents and disease modifying strategies to slow the progress of neurodegeneration. However, due to lack of data about the main pathological sequence of PD, many drug targets failed to provide neuroprotective effects in human trials. Recent evidence suggests the involvement of C-Abelson (c-Abl) tyrosine kinase enzyme in the pathogenesis of PD. Through parkin inactivation, alpha synuclein aggregation, and impaired autophagy of toxic elements. Experimental studies showed that (1) c-Abl activation is involved in neurodegeneration and (2) c-Abl inhibition shows neuroprotective effects and prevents dopaminergic neuronal' death. Current evidence from experimental studies and the first in-human trial shows that c-Abl inhibition holds the promise for neuroprotection against PD and therefore, justifies the movement towards larger clinical trials. In this review article, we discussed the role of c-Abl in PD pathogenesis and the findings of preclinical experiments and the first in-human trial. In addition, based on lessons from the last decade and current preclinical evidence, we provide recommendations for future research in this area.

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 The Role of Pathogens and Anti-Infective Agents in Parkinson’s Disease, from Etiology to Therapeutic Implications

2021 ◽  
pp. 1-18
Author(s):  
Si Shen ◽  
Chan Zhang ◽  
Yu-ming Xu ◽  
Chang-he Shi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Current Evidence ◽  
Long Term Effects ◽  
Neuroprotective Effects ◽  
Therapeutic Implications ◽  
Effective Treatments

Parkinson’s disease is a debilitating neurodegenerative disorder whose etiology is still unclear, hampering the development of effective treatments. There is an urgent need to identify the etiology and provide further effective treatments. Recently, accumulating evidence has indicated that infection may play a role in the etiology of Parkinson’s disease. The infective pathogens may act as a trigger for Parkinson’s disease, the most common of which are hepatitis C virus, influenza virus, and Helicobacter pylori. In addition, gut microbiota is increasingly recognized to influence brain function through the gut-brain axis, showing an important role in the pathogenesis of Parkinson’s disease. Furthermore, a series of anti-infective agents exhibit surprising neuroprotective effects via various mechanisms, such as interfering with α-synuclein aggregation, inhibiting neuroinflammation, attenuating oxidative stress, and preventing from cell death, independent of their antimicrobial effects. The pleiotropic agents affect important events in the pathogenesis of Parkinson’s disease. Moreover, most of them are less toxic, clinically safe and have good blood-brain penetrability, making them hopeful candidates for the treatment of Parkinson’s disease. However, the use of antibiotics and subsequent gut dysbiosis may also play a role in Parkinson’s disease, making the long-term effects of anti-infective drugs worthy of further consideration and exploration. This review summarizes the current evidence for the association between infective pathogens and Parkinson’s disease and subsequently explores the application prospects of anti-infective drugs in Parkinson’s disease treatment, providing novel insights into the pathogenesis and treatment of Parkinson’s disease.

scholarly journals Baicalin Represses C/EBPβ via Its Antioxidative Effect in Parkinson’s Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Kecheng Lei ◽  
Yijue Shen ◽  
Yijing He ◽  
Liwen Zhang ◽  
Jingxing Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
High Efficiency ◽  
Expression Profiles ◽  
Redox Homeostasis ◽  
Lewy Bodies ◽  
Scutellaria Baicalensis Georgi ◽  
Main Component

Parkinson’s disease (PD) is a neurodegenerative disease characterized by the gradual loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the formation of intracellular Lewy bodies (LB) in the brain, which aggregates α-synuclein (α-Syn) as the main component. The interest of flavonoids as potential neuroprotective agents is increasing due to its high efficiency and low side effects. Baicalin is one of the flavonoid compounds, which is a predominant flavonoid isolated from Scutellaria baicalensis Georgi. However, the key molecular mechanism by which Baicalin can prevent the PD pathogenesis remains unclear. In this study, we used bioinformatic assessment including Gene Ontology (GO) to elucidate the correlation between oxidative stress and PD pathogenesis. RNA-Seq methods were used to examine the global expression profiles of noncoding RNAs and found that C/EBPβ expression was upregulated in PD patients compared with healthy controls. Interestingly, Baicalin could protect DA neurons against reactive oxygen species (ROS) and decreased C/EBPβ and α-synuclein expression in pLVX-Tet3G-α-synuclein SH-SY5Y cells. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mouse model, the results revealed that treatment with Baicalin improved the PD model’s behavioral performance and reduced dopaminergic neuron loss in the substantia nigra, associated with the inactivation of proinflammatory cytokines and oxidative stress. Hence, our study supported that Baicalin repressed C/EBPβ via redox homeostasis, which may be an effective potential treatment for PD.

scholarly journals A More Homogeneous Phenotype in Parkinson's Disease Related to R1441G Mutation in the LRRK2 Gene

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana Vinagre-Aragón ◽  
David Campo-Caballero ◽  
Elisabet Mondragón-Rezola ◽  
Lara Pardina-Vilella ◽  
Haizea Hernandez Eguiazu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Association Studies ◽  
Significant Risk ◽  
Lewy Bodies ◽  
Genome Wide Association Studies ◽  
Clinical Heterogeneity ◽  
Therapeutic Implications ◽  
Genome Wide ◽  
Number Of Patients

Parkinson's disease (PD) is characterized by a great clinical heterogeneity. Nevertheless, the biological drivers of this heterogeneity have not been completely elucidated and are likely to be complex, arising from interactions between genetic, epigenetic, and environmental factors. Despite this heterogeneity, the clinical patterns of monogenic forms of PD have usually maintained a good clinical correlation with each mutation once a sufficient number of patients have been studied. Mutations in LRRK2 are the most commonly known genetic cause of autosomal dominant PD known to date. Furthermore, recent genome-wide association studies have revealed variations in LRRK2 as significant risk factors also for the development of sporadic PD. The LRRK2-R1441G mutation is especially frequent in the population of Basque ascent based on a possible founder effect, being responsible for almost 50% of cases of familial PD in our region, with a high penetrance. Curiously, Lewy bodies, considered the neuropathological hallmark of PD, are absent in a significant subset of LRRK2-PD cases. Indeed, these cases appear to be associated with a less aggressive primarily pure motor phenotype. The aim of our research is to examine the clinical phenotype of R1441G-PD patients, more homogeneous when we compare it with sporadic PD patients or with patients carrying other LRRK2 mutations, and reflect on the value of the observed correlation in the genetic forms of PD. The clinical heterogeneity of PD leads us to think that there may be as many different diseases as the number of people affected. Undoubtedly, genetics constitutes a relevant key player, as it may significantly influence the phenotype, with differences according to the mutation within the same gene, and not only in familial PD but also in sporadic forms. Thus, extending our knowledge regarding genetic forms of PD implies an expansion of knowledge regarding sporadic forms, and this may be relevant due to the future therapeutic implications of all forms of PD.

Differences in glucose metabolism between dementia with Lewy bodies and dementia associated with Parkinson's disease

2005 ◽  
Vol 32 (S 4) ◽  
Author(s):  
P Häussermann ◽  
A.O Ceballos-Baumann ◽  
H Förstl ◽  
R Feurer ◽  
B Conrad ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Glucose Metabolism ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies
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