scholarly journals TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Anastazja M. Gorecki ◽  
Chidozie C. Anyaegbu ◽  
Ryan S. Anderton
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Intestinal Barrier ◽  
The Body ◽  
Enteric Neurons ◽  
Gut Dysfunction ◽  
Gut Homeostasis ◽  
The Brain

AbstractParkinson’s disease (PD) is an incurable, devastating disorder that is characterized by pathological protein aggregation and neurodegeneration in the substantia nigra. In recent years, growing evidence has implicated the gut environment and the gut-brain axis in the pathogenesis and progression of PD, especially in a subset of people who exhibit prodromal gastrointestinal dysfunction. Specifically, perturbations of gut homeostasis are hypothesized to contribute to α-synuclein aggregation in enteric neurons, which may spread to the brain over decades and eventually result in the characteristic central nervous system manifestations of PD, including neurodegeneration and motor impairments. However, the mechanisms linking gut disturbances and α-synuclein aggregation are still unclear. A plethora of research indicates that toll-like receptors (TLRs), especially TLR2 and TLR4, are critical mediators of gut homeostasis. Alongside their established role in innate immunity throughout the body, studies are increasingly demonstrating that TLR2 and TLR4 signalling shapes the development and function of the gut and the enteric nervous system. Notably, TLR2 and TLR4 are dysregulated in patients with PD, and may thus be central to early gut dysfunction in PD. To better understand the putative contribution of intestinal TLR2 and TLR4 dysfunction to early α-synuclein aggregation and PD, we critically discuss the role of TLR2 and TLR4 in normal gut function as well as evidence for altered TLR2 and TLR4 signalling in PD, by reviewing clinical, animal model and in vitro research. Growing evidence on the immunological aetiology of α-synuclein aggregation is also discussed, with a focus on the interactions of α-synuclein with TLR2 and TLR4. We propose a conceptual model of PD pathogenesis in which microbial dysbiosis alters the permeability of the intestinal barrier as well as TLR2 and TLR4 signalling, ultimately leading to a positive feedback loop of chronic gut dysfunction promoting α-synuclein aggregation in enteric and vagal neurons. In turn, α-synuclein aggregates may then migrate to the brain via peripheral nerves, such as the vagal nerve, to contribute to neuroinflammation and neurodegeneration typically associated with PD.

scholarly journals Holistic Metabolomic Laboratory-Developed Test (LDT): Development and Use for the Diagnosis of Early-Stage Parkinson’s Disease

Metabolites ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 14
Author(s):  
Petr G. Lokhov ◽  
Dmitry L. Maslov ◽  
Steven Lichtenberg ◽  
Oxana P. Trifonova ◽  
Elena E. Balashova
Keyword(s):  
Parkinson’S Disease ◽  
Molecular Weight ◽  
Parkinson's Disease ◽  
High Resolution Mass Spectrometry ◽  
Early Stage ◽  
Disease Diagnosis ◽  
The Body ◽  
Low Molecular Weight ◽  
Low Molecular Weight Compounds

A laboratory-developed test (LDT) is a type of in vitro diagnostic test that is developed and used within a single laboratory. The holistic metabolomic LDT integrating the currently available data on human metabolic pathways, changes in the concentrations of low-molecular-weight compounds in the human blood during diseases and other conditions, and their prevalent location in the body was developed. That is, the LDT uses all of the accumulated metabolic data relevant for disease diagnosis and high-resolution mass spectrometry with data processing by in-house software. In this study, the LDT was applied to diagnose early-stage Parkinson’s disease (PD), which currently lacks available laboratory tests. The use of the LDT for blood plasma samples confirmed its ability for such diagnostics with 73% accuracy. The diagnosis was based on relevant data, such as the detection of overrepresented metabolite sets associated with PD and other neurodegenerative diseases. Additionally, the ability of the LDT to detect normal composition of low-molecular-weight compounds in blood was demonstrated, thus providing a definition of healthy at the molecular level. This LDT approach as a screening tool can be used for the further widespread testing for other diseases, since ‘omics’ tests, to which the metabolomic LDT belongs, cover a variety of them.

scholarly journals Alpha-synuclein alters the faecal viromes of rats in a gut-initiated model of Parkinson’s disease

2021 ◽  
Author(s):  
S. R. Stockdale ◽  
L. A. Draper ◽  
S. M. O’Donovan ◽  
W. Barton ◽  
O. O’Sullivan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Lewy Body ◽  
Neurological Disorder ◽  
Alpha Synuclein ◽  
Observational Period ◽  
Β Diversity ◽  
Potential Trigger ◽  
The Brain

AbstractParkinson’s disease (PD) is a chronic neurological disorder associated with the misfolding of alpha-synuclein (α-syn) into Lewy body aggregates within nerve cells that contribute to their neurodegeneration. Recent evidence suggests α-syn aggregation may begin in the gut and travel to the brain along the vagus nerve, with microbes a potential trigger initiating the misfolding of α-syn. However, changes in the gut virome in response to α-syn alterations have not been investigated. In this study, we show longitudinal changes in the faecal virome of rats administered either monomeric or preformed fibrils (PFF) of α-syn directly into their enteric nervous system. Differential changes in rat viromes were observed when comparing monomeric and PFF α-syn. The virome β-diversity changes after α-syn treatment were compounded by the addition of LPS as an adjunct. Changes in the diversity of rat faecal viromes were observed after one month and did not resolve within the study’s five month observational period. Overall, these results suggest that microbiome alterations associated with PD may, partially, be reactive to host α-syn associated changes.

scholarly journals What Is the Evidence that Parkinson’s Disease Is a Prion Disorder, Which Originates in the Gut?

2018 ◽  
Vol 19 (11) ◽  
pp. 3573 ◽  
Author(s):  
Małgorzata Kujawska ◽  
Jadwiga Jodynis-Liebert
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Neurodegenerative Disorder ◽  
Human Subjects ◽  
Gastrointestinal Symptoms ◽  
Convincing Evidence ◽  
Substantia Nigra Pars Compacta ◽  
Motor Nucleus ◽  
The Brain

Parkinson’s disease (PD) is a neurodegenerative disorder resulting from degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). PD is characterized by motor dysfunctions as well as gastrointestinal symptoms and mental impairment. The pathological hallmark of PD is an accumulation of misfolded α-synuclein aggregates within the brain. The etiology of PD and related synucleinopathy is poorly understood, but recently, the hypothesis that α-synuclein pathology spreads in a prion-like fashion originating in the gut has gained much scientific attention. A crucial clue was the appearance of constipation before the onset of motor symptoms, gut dysbiosis and synucleinopathy in PD patients. Another line of evidence, demonstrating accumulation of α-synuclein within the peripheral autonomic nervous system (PANS), including the enteric nervous system (ENS), and the dorsal motor nucleus of the vagus (DMV) support the concept that α-synuclein can spread from the ENS to the brain by the vagus nerve. The decreased risk of PD following truncal vagotomy supports this. The convincing evidence of the prion-like behavior of α-synuclein came from postmortem observations that pathological α-synuclein inclusions appeared in healthy grafted neurons. In this review, we summarize the available data from human subjects’ research and animal experiments, which seem to be the most suggestive for explaining the hypotheses.

scholarly journals Parkinson’s disease is a type of amyloidosis featuring accumulation of amyloid fibrils of α-synuclein

2019 ◽  
Vol 116 (36) ◽  
pp. 17963-17969 ◽  
Author(s):  
Katsuya Araki ◽  
Naoto Yagi ◽  
Koki Aoyama ◽  
Chi-Jing Choong ◽  
Hideki Hayakawa ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amyloid Fibrils ◽  
Lewy Bodies ◽  
X Ray Diffraction ◽  
Thin Sections ◽  
X Ray ◽  
Β Sheet ◽  
The Brain

Many neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates in the brain. In Parkinson’s disease (PD), α-synuclein (α-syn) forms such aggregates called Lewy bodies (LBs). Recently, it has been reported that aggregates of α-syn with a cross-β structure are capable of propagating within the brain in a prionlike manner. However, the presence of cross-β sheet-rich aggregates in LBs has not been experimentally demonstrated so far. Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and found that some of them gave a diffraction pattern typical of a cross-β structure. This result confirms that LBs in the brain of PD patients contain amyloid fibrils with a cross-β structure and supports the validity of in vitro propagation experiments using artificially formed amyloid fibrils of α-syn. Notably, our finding supports the concept that PD is a type of amyloidosis, a disease featuring the accumulation of amyloid fibrils of α-syn.

scholarly journals α-synuclein pathogenesis in hiPSC models of Parkinson’s Disease

2021 ◽  
Author(s):  
Leo R Quinlan ◽  
Jara Maria Baena-Montes ◽  
Sahar Avazzadeh
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Modeling ◽  
Viral Vector ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Model Systems ◽  
The Brain

α-synuclein is an increasingly prominent player in the pathology of a variety of neurodegenerative conditions. Parkinson’s disease (PD) is a neurodegenerative disorder that affects mainly the dopaminergic neurons in the substantia nigra of the brain. Typical of PD pathology is the finding of protein aggregations termed ‘Lewy bodies’ in the brain regions affected. α-synuclein is implicated in many disease states including dementia with Lewy bodies and Alzheimer’s disease. However, PD is the most common synucleinopathy and continues to be a significant focus of PD research in terms of the α-synuclein Lewy body pathology. Mutations in several genes are associated with PD development including SNCA, which encodes α-synuclein. A variety of model systems have been employed to study α-synuclein physiology and pathophysiology in an attempt to relate more closely to PD pathology. These models include cellular and animal system exploring transgenic technologies, viral vector expression and knockdown approaches, and models to study the potential prion protein-like effects of α-synuclein. The current review focuses on human induced pluripotent stem cell (iPSC) models with a specific focus on mutations or multiplications of the SNCA gene. iPSCs are a rapidly evolving technology with huge promise in the study of normal physiology and disease modeling in vitro. The ability to maintain a patient's genetic background and replicate similar cell phenotypes make iPSCs a powerful tool in the study of neurological diseases. This review focus on the current knowledge about α-synuclein physiological function as well as its role in PD pathogenesis based on human iPSC models.

Fractionally delineate the neuroprotective function of calbindin-D28k in Parkinson’s disease

2018 ◽  
Vol 11 (08) ◽  
pp. 1850103 ◽  
Author(s):  
Hardik Joshi ◽  
Brajesh Kumar Jha
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dimensional Space ◽  
Cytosolic Calcium ◽  
The Body ◽  
Dopamine Neurons ◽  
Reaction Diffusion Equation ◽  
Substantia Nigra Pars Compacta ◽  
Brain Disorder ◽  
The Brain

Neuron is a fundamental unit of the brain, which is specialized to transmit information throughout the body through electrical and chemical signals. Calcium ([Formula: see text]) ions are known as second messengers which play important roles in the movement of the neurotransmitter. Calbindin-[Formula: see text] is a [Formula: see text] binding protein which is involved in regulation of intracellular [Formula: see text] ions and maintains [Formula: see text] homeostasis level, it also alters the cytosolic calcium concentration ([[Formula: see text]]) in nerve cells to keep the cell alive. Parkinson’s disease (PD) is a chronic progressive neurodegenerative brain disorder of the nervous system. Several regions of the brain indicate the hallmark of the PD. The symptoms of PD are plainly linked with the degeneration and death of dopamine neurons in the substantia nigra pars compacta located in midbrain which is accompanied by depletion in calbindin-[Formula: see text]. In the present paper, the neuroprotective role of calbindin-[Formula: see text] in the cytoplasmic [[Formula: see text]] distribution is studied. The elicitation in [[Formula: see text]] is due to the presence of low amount of calbindin-[Formula: see text] which can be portrayed and is a hallmark of PD. A one-dimensional space time fractional reaction diffusion equation is designed by keeping in mind the physiological condition taking place inside Parkinson’s brain. Computational results are performed in MATLAB.

Orally Administered Nanotherapeutics For Parkinson’s Disease: An Old Delivery System Yet More Acceptable

2020 ◽  
Vol 26 (19) ◽  
pp. 2280-2290 ◽  
Author(s):  
Nidhi Aggarwal ◽  
Zufika Qamar ◽  
Saleha Rehman ◽  
Sanjula Baboota ◽  
Javed Ali
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Drug Delivery Systems ◽  
Neurodegenerative Disorder ◽  
Intestinal Barrier ◽  
Oral Route ◽  
Delivery Systems ◽  
The Body ◽  
Area Of Interest

As per the present global scenario, Parkinson’s disease (PD) is considered to be the second most common neurodegenerative disorder which is a keen area of interest among researchers. The conventional therapies generally employed against PD are associated with serious drawbacks including limited transport across selectively permeable BBB, hepatic metabolism, intestinal barrier, etc. This urges the need to develop novel therapeutic alternatives. The oral route being the most preferred route of administration needs to be explored for new and more intelligent drug delivery systems. Nanotechnology has been proposed to play a promising role in reversing the progression of the disease via the oral route. Nanocarriers, namely nanoparticles, lipid nanoparticles, nanoemulsions, nanocrystals, nanomicellar formulations, self-nanoemulsifying drug delivery systems and alginate nanocomposites have been investigated upon to modulate the fate of drugs inside the human body when administered orally. The development of various nanotherapeutics for the treatment of PD has been reviewed, depicting an enhanced bioavailability to provide a desired therapeutic outcome. The new advances in the therapy have been explored and highlighted through the body of this review. However, a therapeutically effective concentration at the target site remains a challenge, therefore extensive exploration in the field of nanotherapeutics may facilitate superior drug delivery to CNS via oral route thereby improving the state of disease progression.

scholarly journals Parkinson’s disease recovery by GM1 oligosaccharide treatment in the B4galnt1+/− mouse model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Elena Chiricozzi ◽  
Laura Mauri ◽  
Giulia Lunghi ◽  
Erika Di Biase ◽  
Maria Fazzari ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Therapeutic Potential ◽  
Physical Symptoms ◽  
Wild Type ◽  
Ganglioside Content ◽  
Sporadic Parkinson’S Disease ◽  
Specific Membrane ◽  
The Brain

AbstractGiven the recent in vitro discovery that the free soluble oligosaccharide of GM1 is the bioactive portion of GM1 for neurotrophic functions, we investigated its therapeutic potential in the B4galnt1+/− mice, a model of sporadic Parkinson’s disease. We found that the GM1 oligosaccharide, systemically administered, reaches the brain and completely rescues the physical symptoms, reduces the abnormal nigral α-synuclein content, restores nigral tyrosine hydroxylase expression and striatal neurotransmitter levels, overlapping the wild-type condition. Thus, this study supports the idea that the Parkinson’s phenotype expressed by the B4galnt1+/− mice is due to a reduced level of neuronal ganglioside content and lack of interactions between the oligosaccharide portion of GM1 with specific membrane proteins. It also points to the therapeutic potential of the GM1 oligosaccharide for treatment of sporadic Parkinson’s disease.

scholarly journals MICROBIOTA INTESTINAL RELACIONADA A DOENÇA DE PARKINSON

2021 ◽  
Vol 5 (1) ◽  
pp. 49-60
Author(s):  
Caroline Felix da Silva ◽  
Graziele Estevo Azevedo ◽  
Natália Franco Taketani
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gastrointestinal Tract ◽  
Intestinal Microbiota ◽  
Direct Relationship ◽  
Progressive Disease ◽  
Signs And Symptoms ◽  
The Body ◽  
Early Age ◽  
The Brain

RESUMO. A Doença de Parkinson é uma doença crônica, neurodegenerativa e progressiva onde não tem cura. Ainda há muitas investigações para se descobrir a causa da patologia. Em estudos recentes descobriram que pode ter uma relação direta com intestino, com a possibilidade de origem na microbiota intestinal e espalhando-se até o cérebro, com relação a uma desregulação no trato gastrointestinal. É reconhecido que, antes de aparecer os sinais e sintomas motores da doença, o organismo começa a sofrer alterações desde cedo, como a constipação intestinal, com o fortalecimento da hipótese de que a doença de Parkinson tenha início no trato gastrointestinal, e chegue até o cérebro através do nervo vago. Este trabalho pretende abordar sobre a microbiota intestinal e a sua conexão com a doença de Parkinson fazendo revisão de estudos e evidência de como sua composição no hospedeiro pode influenciar o seu metabolismo. A modulação da microbiota intestinal poderá, então, ser uma estratégia para o desenvolvimento de novas opções terapêuticas para o tratamento de doenças neurodegenerativas. ABSTRACT. Parkinson's Disease is a chronic, neurodegenerative and progressive disease that has no cure. There are still many investigations to discover the cause of the pathology. In recent studies they found that it may have a direct relationship with the intestine, with the possibility of originating in the intestinal microbiota and spreading to the brain, with respect to dysregulation in the gastrointestinal tract. It is recognized that, before the appearance of the motor signs and symptoms of the disease, the body begins to undergo changes from an early age, such as intestinal constipation, with the strengthening of the hypothesis that Parkinson's disease starts in the gastrointestinal tract and reaches the brain through the vagus nerve. This work intends to approach the intestinal microbiota and its connection with Parkinson's disease, reviewing studies and evidence on how its composition in the host can influence its metabolism. The modulation of the intestinal microbiota could then be a strategy for the development of new therapeutic options for the treatment of neurodegenerative diseases.

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