scholarly journals The Contribution ofα-Synuclein Spreading to Parkinson’s Disease Synaptopathy

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Francesca Longhena ◽  
Gaia Faustini ◽  
Cristina Missale ◽  
Marina Pizzi ◽  
PierFranco Spano ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorders ◽  
Physiological Conditions ◽  
Age Related ◽  
Endogenous Protein ◽  
Synaptic Failure ◽  
Nigrostriatal Neurons ◽  
Somatic Nervous System ◽  
The Brain

Synaptopathies are diseases with synapse defects as shared pathogenic features, encompassing neurodegenerative disorders such as Parkinson’s disease (PD). In sporadic PD, the most common age-related neurodegenerative movement disorder, nigrostriatal dopaminergic deficits are responsible for the onset of motor symptoms that have been related toα-synuclein deposition at synaptic sites. Indeed,α-synuclein accumulation can impair synaptic dopamine release and induces the death of nigrostriatal neurons. While in physiological conditions the protein can interact with and modulate synaptic vesicle proteins and membranes, numerous experimental evidences have confirmed that its pathological aggregation can compromise correct neuronal functioning. In addition, recent findings indicate thatα-synuclein pathology spreads into the brain and can affect the peripheral autonomic and somatic nervous system. Indeed, monomeric, oligomeric, and fibrillaryα-synuclein can move from cell to cell and can trigger the aggregation of the endogenous protein in recipient neurons. This novel “prion-like” behavior could further contribute to synaptic failure in PD and other synucleinopathies. This review describes the major findings supporting the occurrence ofα-synuclein pathology propagation in PD and discusses how this phenomenon could induce or contribute to synaptic injury and degeneration.

scholarly journals Insights into the multifaceted role of circular RNAs: implications for Parkinson’s disease pathogenesis and diagnosis

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Epaminondas Doxakis
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Clinical Manifestations ◽  
Alpha Synuclein ◽  
Circular Rnas ◽  
Age Related ◽  
And Function ◽  
The Brain

AbstractParkinson’s disease (PD) is a complex, age-related, neurodegenerative disease whose etiology, pathology, and clinical manifestations remain incompletely understood. As a result, care focuses primarily on symptoms relief. Circular RNAs (circRNAs) are a large class of mostly noncoding RNAs that accumulate with aging in the brain and are increasingly shown to regulate all aspects of neuronal and glial development and function. They are generated by the spliceosome through the backsplicing of linear RNA. Although their biological role remains largely unknown, they have been shown to regulate transcription and splicing, act as decoys for microRNAs and RNA binding proteins, used as templates for translation, and serve as scaffolding platforms for signaling components. Considering that they are stable, diverse, and detectable in easily accessible biofluids, they are deemed promising biomarkers for diagnosing diseases. CircRNAs are differentially expressed in the brain of patients with PD, and growing evidence suggests that they regulate PD pathogenetic processes. Here, the biogenesis, expression, degradation, and detection of circRNAs, as well as their proposed functions, are reviewed. Thereafter, research linking circRNAs to PD-related processes, including aging, alpha-synuclein dysregulation, neuroinflammation, and oxidative stress is highlighted, followed by recent evidence for their use as prognostic and diagnostic biomarkers for PD.

scholarly journals Extracellular Vesicles in Alzheimer’s and Parkinson’s Disease: Small Entities with Large Consequences

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2485
Author(s):  
Charysse Vandendriessche ◽  
Arnout Bruggeman ◽  
Caroline Van Cauwenberghe ◽  
Roosmarijn E. Vandenbroucke
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Progression ◽  
Extracellular Vesicles ◽  
Neurodegenerative Disorders ◽  
Neuronal Damage ◽  
Protein Aggregates ◽  
Pathological Changes ◽  
Associated Proteins ◽  
The Brain

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are incurable, devastating neurodegenerative disorders characterized by the formation and spreading of protein aggregates throughout the brain. Although the exact spreading mechanism is not completely understood, extracellular vesicles (EVs) have been proposed as potential contributors. Indeed, EVs have emerged as potential carriers of disease-associated proteins and are therefore thought to play an important role in disease progression, although some beneficial functions have also been attributed to them. EVs can be isolated from a variety of sources, including biofluids, and the analysis of their content can provide a snapshot of ongoing pathological changes in the brain. This underlines their potential as biomarker candidates which is of specific relevance in AD and PD where symptoms only arise after considerable and irreversible neuronal damage has already occurred. In this review, we discuss the known beneficial and detrimental functions of EVs in AD and PD and we highlight their promising potential to be used as biomarkers in both diseases.

scholarly journals Interactions Between MPTP-Induced and Age-Related Neuronal Death in a Murine Model of Parkinson’s Disease

1992 ◽  
Vol 19 (S1) ◽  
pp. 124-133 ◽  
Author(s):  
William G. Tatton ◽  
Carol E. Greenwood ◽  
Nadine A. Seniuk ◽  
Paul T. Salo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Time Course ◽  
Neurological Deficits ◽  
Dopamine Synthesis ◽  
Exponential Relationship ◽  
Axon Terminals ◽  
Age Related ◽  
Nigrostriatal Neurons ◽  
Methyl Phenyl Tetrahydropyridine

ABSTRACT:Abiotrophy is hypothesized to explain the onset and time course of deficits in Parkinson’s disease (PD) Abiotrophy includes: 1) exposure to agent(s) causing the death of dopaminergic nigrostriatal neurons (DNSns), 2) gradual death of DNSns with age, 3) summation of 1) and 2) until DNSn numbers fall below a threshold for detectable neurological deficits. Murine DNSn death following methyl-phenyl-tetrahydropyridine (MPTP) exposure occurs according to an exponential relationship while age-related death of DNSns occurs according to a second exponential relationship. Summing the two exponential losses overestimates experimental DNSn death showing a simple abiotrophic model is not sufficient. Aged murine DNSns greatly increase their dopamine synthesis and the density of their striatal axon terminals which may explain the above threshold. Murine DNSns die gradually after MPTP exposure and L-deprenyl treatment rescues MPTP-damaged DNSns by a previously undiscovered action, altering the abiotrophic interactions and possibly explaining the slowed progression of PD found with deprenyl treatment.

scholarly journals Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia

2021 ◽  
Vol 14 ◽  
Author(s):  
Melissa Scholefield ◽  
Stephanie J. Church ◽  
Jingshu Xu ◽  
Stefano Patassini ◽  
Federico Roncaroli ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
High Performance ◽  
Neuronal Loss ◽  
Middle Temporal Gyrus ◽  
Parkinson’S Disease Dementia ◽  
Pathogenic Potential ◽  
Age Related ◽  
Liquid Chromatography Tandem Mass ◽  
The Brain

Widespread elevations in brain urea have, in recent years, been reported in certain types of age-related dementia, notably Alzheimer’s disease (AD) and Huntington’s disease (HD). Urea increases in these diseases are substantive, and approximate in magnitude to levels present in uraemic encephalopathy. In AD and HD, elevated urea levels are widespread, and not only in regions heavily affected by neurodegeneration. However, measurements of brain urea have not hitherto been reported in Parkinson’s disease dementia (PDD), a condition which shares neuropathological and symptomatic overlap with both AD and HD. Here we report measurements of tissue urea from nine neuropathologically confirmed regions of the brain in PDD and post-mortem delay (PMD)-matched controls, in regions including the cerebellum, motor cortex (MCX), sensory cortex, hippocampus (HP), substantia nigra (SN), middle temporal gyrus (MTG), medulla oblongata (MED), cingulate gyrus, and pons, by applying ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Urea concentrations were found to be substantively elevated in all nine regions, with average increases of 3–4-fold. Urea concentrations were remarkably consistent across regions in both cases and controls, with no clear distinction between regions heavily affected or less severely affected by neuronal loss in PDD. These urea elevations mirror those found in uraemic encephalopathy, where equivalent levels are generally considered to be pathogenic, and those previously reported in AD and HD. Increased urea is a widespread metabolic perturbation in brain metabolism common to PDD, AD, and HD, at levels equal to those seen in uremic encephalopathy. This presents a novel pathogenic mechanism in PDD, which is shared with two other neurodegenerative diseases.

Sudden unexpected death in Parkinson’s disease: why is drinking water important?

2019 ◽  
Vol 9 (4) ◽  
pp. 241-246 ◽  
Author(s):  
Francisco S Menezes-Rodrigues ◽  
Cristiane S Scorza ◽  
Ana C Fiorini ◽  
Afonso Caricati-Neto ◽  
Carla A Scorza ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drinking Water ◽  
Neurodegenerative Disorders ◽  
Premature Death ◽  
Healthy Controls ◽  
Unexpected Death ◽  
Age Related ◽  
Daily Water ◽  
Daily Water Consumption

Parkinson’s disease (PD) is one of the most common age-related neurodegenerative disorders. Several studies over the last few years have shown that PD is accompanied by high rates of premature death compared with healthy controls. Death in PD patients is usually caused by determinant factors such as pneumonia, and cerebrovascular and cardiovascular diseases. During recent years it has emerged that dehydration may also contribute to mortality in PD. Interestingly, it has been documented that a substantial proportion of patients with PD die suddenly (known as sudden and unexpected death in PD). In this article, we focus on the magnitude of the problem of sudden and unexpected death in PD, with special reference to the daily water consumption of PD patients.

scholarly journals PET Studies of Net Blood—Brain Clearance of FDOPA to Human Brain: Age-Dependent Decline of [18F]Fluorodopamine Storage Capacity

2005 ◽  
Vol 25 (7) ◽  
pp. 807-819 ◽  
Author(s):  
Yoshitaka Kumakura ◽  
Ingo Vernaleken ◽  
Gerhard Gründer ◽  
Peter Bartenstein ◽  
Albert Gjedde ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Storage Capacity ◽  
Compartmental Analysis ◽  
Graphical Analysis ◽  
Negative Bias ◽  
Precursor Pool ◽  
Healthy Elderly ◽  
Age Related ◽  
The Brain

Conventional methods for the graphical analysis of 6-[18F]fluorodopa (FDOPA)/positron emission tomography (PET) recordings ( Kappin) may be prone to negative bias because of oversubtraction of the precursor pool in the region of interest, and because of diffusion of decarboxylated FDOPA metabolites from the brain. These effects may reduce the sensitivity of FDOPA/PET for the detection of age-related changes in dopamine innervations. To test for these biasing effects, we have used a constrained compartmental analysis to calculate the brain concentrations of the plasma metabolite 3- O-methyl-FDOPA (OMFD) during 120 mins of FDOPA circulation in healthy young, healthy elderly, and Parkinson's disease subjects. Calculated brain OMFD concentrations were subtracted frame-by-frame from the dynamic PET recordings, and maps of the FDOPA net influx to brain were calculated assuming irreversible trapping ( Kapp). Comparison of Kappin and Kapp maps revealed a global negative bias in the conventional estimates of FDOPA clearance. The present OMFD subtraction method revealed curvature in plots of Kapp at early times, making possible the calculation of the corrected net influx ( K) and also the rate constant for diffusion of decarboxylated metabolites from the brain ( kloss). The effective distribution volume (EDV2; K/ kloss) for FDOPA, an index of dopamine storage capacity in brain, was reduced by 85% in putamen of patients with Parkinson's disease, and by 58% in the healthy elderly relative to the healthy young control subjects. Results of the present study support claims that storage capacity for dopamine in both caudate and putamen is more profoundly impaired in patients with Parkinson's disease than is the capacity for DOPA utilization, calculated by conventional FDOPA net influx plots. The present results furthermore constitute the first demonstration of an abnormality in the cerebral utilization of FDOPA in caudate and putamen as a function of normal aging, which we attribute to loss of vesicular storage capacity.

scholarly journals S-nitrosylation-impaired autophagy: An alternative mechanism underlying aging?

2013 ◽  
Author(s):  
Qing-Ping Zeng
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorders ◽  
Alternative Mechanism ◽  
Age Related ◽  
Surprising Finding

Aging is mysterious with unknown managing patterns. A surprising finding on the tune mode of autophagy by S-nitrosylation is a distinctive step towards the interpretation of the mechanism underlying aging and age-related diseases. This commentary article will discuss, in a wider sense, the implications of S-nitrosylation- and nitration-switched dysfunction of proteins/enzymes in neurodegenerative disorders including Alzheimer's disease (AD), Huntington's diseases (HD) and Parkinson's disease (PD).

scholarly journals Bidirectional Mendelian randomization analysis of shared genetic signals between coexisting neurodegenerative disorders to decipher underlying causal pathways

2019 ◽  
Author(s):  
Sandeep Grover ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Macular Degeneration ◽  
Neurodegenerative Disorders ◽  
Mendelian Randomization ◽  
Age Related Macular Degeneration ◽  
European Ancestry ◽  
Age Related

ABSTRACTOBJECTIVETo investigate whether coexistence of various neurodegenerative disorders is coincidental or biologically connected.DESIGNTwo sample Mendelian randomization using summary effect estimatesSETTINGGenetic data taken on various neurodegenerative disorders from various cohorts comprising individuals predominantly of European ancestry.PARTICIPANTSInternational Genomics of Alzheimer’s patients (IGAP), project MinE, International Age-related Macular Degeneration Consortium (IAMDGC), International Multiple Sclerosis Genetics Consortium (IMSGC), International Parkinson’s Disease Genomics Consortium (IPDGC)MAIN OUTCOME MEASURESAlzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), Age related macular degeneration (AMD), Multiple sclerosis (MS) and Parkinson’s disease (PD).RESULTSA Bonferroni corrected threshold of P=0.005 was considered to be significant, and P<0.05 was considered suggestive of evidence for a potential association. I observed a risky effect of PD on ALS (OR = 1.126, 95% CI = 1.059-1.198, P = 0.005). Using AD as exposure and PD as outcome, I observed a risky effect of AD on PD using all the MR methods with strongest results using MBE method (OR = 2.072, 95% CI = 1.006-4.028, P = 0.0416). Genetic predisposition to AD was further observed to be a risky for AMD (OR = 1.759, 95% CI = 1.040-1.974, P = 0.0363). On the contrary, AMD was observed to be strongly protective towards MS (OR = 0.861, 95% CI = 0.776-0.955, P = 0.0059).CONCLUSIONSMy findings are consistent with the previously observed relative occurrence of co-existing neurodegenerative diseases or overlapping symptoms among neurodegenerative diseases.

scholarly journals What Is Our Understanding of the Influence of Gut Microbiota on the Pathophysiology of Parkinson’s Disease?

2021 ◽  
Vol 15 ◽  
Author(s):  
Amaryllis E. Hill ◽  
Richard Wade-Martins ◽  
Philip W. J. Burnet
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gut Microbiota ◽  
Neurodegenerative Disorders ◽  
Alpha Synuclein ◽  
Bidirectional Communication ◽  
Enteric Nerves ◽  
The Brain ◽  
Gut Microbiota Dysbiosis ◽  
Bacterial Products

Microbiota have increasingly become implicated in predisposition to human diseases, including neurodegenerative disorders such as Parkinson’s disease (PD). Traditionally, a central nervous system (CNS)-centric approach to understanding PD has predominated; however, an association of the gut with PD has existed since Parkinson himself reported the disease. The gut–brain axis refers to the bidirectional communication between the gastrointestinal tract (GIT) and the brain. Gut microbiota dysbiosis, reported in PD patients, may extend this to a microbiota–gut–brain axis. To date, mainly the bacteriome has been investigated. The change in abundance of bacterial products which accompanies dysbiosis is hypothesised to influence PD pathophysiology via multiple mechanisms which broadly centre on inflammation, a cause of alpha-synuclein (a-syn) misfolding. Two main routes are hypothesised by which gut microbiota can influence PD pathophysiology, the neural and humoral routes. The neural route involves a-syn misfolding peripherally in the enteric nerves which can then be transported to the brain via the vagus nerve. The humoral route involves transportation of bacterial products and proinflammatory cytokines from the gut via the circulation which can cause central a-syn misfolding by inducing neuroinflammation. This article will assess whether the current literature supports gut bacteria influencing PD pathophysiology via both routes.

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