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

Current Knowledge ◽

Lewy Bodies ◽

Model Systems ◽

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.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1906124116 ◽

2019 ◽

Vol 116 (36) ◽

pp. 17963-17969 ◽

Cited By ~ 24

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 ◽

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.

Viral vector delivery of neurotrophic factors for Parkinson's disease therapy

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2015.6 ◽

2015 ◽

Vol 17 ◽

Cited By ~ 20

Author(s):

Martin J. Kelly ◽

Gerard W. O'Keeffe ◽

Aideen M. Sullivan

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clinical Trials ◽

Neurotrophic Factors ◽

Neurotrophic Factor ◽

Dopaminergic Neurons ◽

Viral Vectors ◽

Viral Vector ◽

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the progressive loss of midbrain dopaminergic neurons, which causes motor impairments. Current treatments involve dopamine replacement to address the disease symptoms rather than its cause. Factors that promote the survival of dopaminergic neurons have been proposed as novel therapies for PD. Several dopaminergic neurotrophic factors (NTFs) have been examined for their ability to protect and/or restore degenerating dopaminergic neurons, both in animal models and in clinical trials. These include glial cell line-derived neurotrophic factor, neurturin, cerebral dopamine neurotrophic factor and growth/differentiation factor 5. Delivery of these NTFs via injection or infusion to the brain raises several practical problems. A new delivery approach for NTFs involves the use of recombinant viral vectors to enable long-term expression of these factors in brain cells. Vectors used include those based on adenoviruses, adeno-associated viruses and lentiviruses. Here we review progress to date on the potential of each of these four NTFs as novel therapeutic strategies for PD, as well as the challenges that have arisen, from pre-clinical analysis to clinical trials. We conclude by discussing recently-developed approaches to optimise the delivery of NTF-carrying viral vectors to the brain.

The Gut–Brain Axis and Its Relation to Parkinson’s Disease: A Review

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.782082 ◽

2022 ◽

Vol 13 ◽

Author(s):

Emily M. Klann ◽

Upuli Dissanayake ◽

Anjela Gurrala ◽

Matthew Farrer ◽

Aparna Wagle Shukla ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Current Knowledge ◽

Lewy Bodies ◽

Disease Diagnosis ◽

Alpha Synuclein ◽

Motor Symptoms ◽

Abnormal Gait ◽

Non Motor Symptoms ◽

Parkinson’s disease is a chronic neurodegenerative disease characterized by the accumulation of misfolded alpha-synuclein protein (Lewy bodies) in dopaminergic neurons of the substantia nigra and other related circuitry, which contribute to the development of both motor (bradykinesia, tremors, stiffness, abnormal gait) and non-motor symptoms (gastrointestinal issues, urinogenital complications, olfaction dysfunction, cognitive impairment). Despite tremendous progress in the field, the exact pathways and mechanisms responsible for the initiation and progression of this disease remain unclear. However, recent research suggests a potential relationship between the commensal gut bacteria and the brain capable of influencing neurodevelopment, brain function and health. This bidirectional communication is often referred to as the microbiome–gut–brain axis. Accumulating evidence suggests that the onset of non-motor symptoms, such as gastrointestinal manifestations, often precede the onset of motor symptoms and disease diagnosis, lending support to the potential role that the microbiome–gut–brain axis might play in the underlying pathological mechanisms of Parkinson’s disease. This review will provide an overview of and critically discuss the current knowledge of the relationship between the gut microbiota and Parkinson’s disease. We will discuss the role of α-synuclein in non-motor disease pathology, proposed pathways constituting the connection between the gut microbiome and the brain, existing evidence related to pre- and probiotic interventions. Finally, we will highlight the potential opportunity for the development of novel preventative measures and therapeutic options that could target the microbiome–gut–brain axis in the context of Parkinson’s disease.

Parkinson’s Disease-Overview

Journal of Regenerative Biology and Medicine ◽

10.37191/mapsci-2582-385x-3(6)-092 ◽

2021 ◽

Author(s):

Fariha Khaliq

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Modeling ◽

Disease Risk ◽

Lewy Bodies ◽

In Vivo Studies ◽

Common Genetic Variants

Parkinson’s disease one of the most complex neurological disorder. The disease risk and progression are due to common genetic variants. Approximately 6.2 million cases are reported each year according to the statistics published in 2015 whereas it is expected that this number will be twice by 2040. There are two types of Parkinson’s disease, familial Parkinson’s disease, and sporadic Parkinson’s disease. The disease is characterized by the presence of Lewy bodies. Adult age increases the risk of Parkinson’s disease. In this review, we provide an overview of the disease pathology of Lewy bodies in the occurrence of Parkinson’s disease, in vitro studies to determine the role of iPSCs in treatment of Parkinson’s disease, in vivo studies to determine the role of animal model in studying disease modeling, and future prospective how single-cell RNA sequencing technology is a major advancement in studying and find the treatment for Parkinson’s disease.

Neurotoxic and Neuroprotective Role of Exosomes in Parkinson’s Disease

Current Pharmaceutical Design ◽

10.2174/1381612825666191113103537 ◽

2020 ◽

Vol 25 (42) ◽

pp. 4510-4522 ◽

Cited By ~ 5

Author(s):

Biancamaria Longoni ◽

Irene Fasciani ◽

Shivakumar Kolachalam ◽

Ilaria Pietrantoni ◽

Francesco Marampon ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Potential Role ◽

Current Knowledge ◽

Biological Fluids ◽

Cell Communication ◽

Target Cells ◽

Cellular Debris ◽

: Exosomes are extracellular vesicles produced by eukaryotic cells that are also found in most biological fluids and tissues. While they were initially thought to act as compartments for removal of cellular debris, they are now recognized as important tools for cell-to-cell communication and for the transfer of pathogens between the cells. They have attracted particular interest in neurodegenerative diseases for their potential role in transferring prion-like proteins between neurons, and in Parkinson’s disease (PD), they have been shown to spread oligomers of α-synuclein in the brain accelerating the progression of this pathology. A potential neuroprotective role of exosomes has also been equally proposed in PD as they could limit the toxicity of α-synuclein by clearing them out of the cells. Exosomes have also attracted considerable attention for use as drug vehicles. Being nonimmunogenic in nature, they provide an unprecedented opportunity to enhance the delivery of incorporated drugs to target cells. In this review, we discuss current knowledge about the potential neurotoxic and neuroprotective role of exosomes and their potential application as drug delivery systems in PD.

Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders

Acta Neuropathologica ◽

10.1007/s00401-021-02266-7 ◽

2021 ◽

Cited By ~ 1

Author(s):

Daniel Erskine ◽

David Koss ◽

Viktor I. Korolchuk ◽

Tiago F. Outeiro ◽

Johannes Attems ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lewy Bodies ◽

Mitochondrial Diseases ◽

Model Systems ◽

Lipid Homeostasis ◽

Lysosomal Storage ◽

Iron Storage ◽

Monogenic Disorders ◽

Storage Disorders

AbstractAccumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.

Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson’s Disease

Cells ◽

10.3390/cells10020283 ◽

2021 ◽

Vol 10 (2) ◽

pp. 283

Author(s):

Daniel Aghaie Madsen ◽

Sissel Ida Schmidt ◽

Morten Blaabjerg ◽

Morten Meyer

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Ubiquitin Ligase ◽

Current Knowledge ◽

Lewy Bodies ◽

Ubiquitin Proteasome System ◽

Loss Of Function ◽

Functional Interaction ◽

Future Studies ◽

Ubiquitin Proteasome

Parkin and α-synuclein are two key proteins involved in the pathophysiology of Parkinson’s disease (PD). Neurotoxic alterations of α-synuclein that lead to the formation of toxic oligomers and fibrils contribute to PD through synaptic dysfunction, mitochondrial impairment, defective endoplasmic reticulum and Golgi function, and nuclear dysfunction. In half of the cases, the recessively inherited early-onset PD is caused by loss of function mutations in the PARK2 gene that encodes the E3-ubiquitin ligase, parkin. Parkin is involved in the clearance of misfolded and aggregated proteins by the ubiquitin-proteasome system and regulates mitophagy and mitochondrial biogenesis. PARK2-related PD is generally thought not to be associated with Lewy body formation although it is a neuropathological hallmark of PD. In this review article, we provide an overview of post-mortem neuropathological examinations of PARK2 patients and present the current knowledge of a functional interaction between parkin and α-synuclein in the regulation of protein aggregates including Lewy bodies. Furthermore, we describe prevailing hypotheses about the formation of intracellular micro-aggregates (synuclein inclusions) that might be more likely than Lewy bodies to occur in PARK2-related PD. This information may inform future studies aiming to unveil primary signaling processes involved in PD and related neurodegenerative disorders.

Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjaa075 ◽

2021 ◽

Author(s):

Maarten C Hardenberg ◽

Tessa Sinnige ◽

Sam Casford ◽

Samuel Dada ◽

Chetan Poudel ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Self Assembly ◽

Lewy Body ◽

Amyloid Fibrils ◽

Liquid Droplet ◽

Large Body ◽

Lewy Bodies ◽

Cellular Components

Abstract Misfolded α-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson’s disease. A large body of evidence shows that α-synuclein can aggregate into amyloid fibrils, but the relationship between α-synuclein self-assembly and Lewy body formation remains unclear. Here we show, both in vitro and in a Caenorhabditis elegans model of Parkinson’s disease, that α-synuclein undergoes liquid‒liquid phase separation by forming a liquid droplet state, which converts into an amyloid-rich hydrogel with Lewy-body-like properties. This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro. Taken together, these results suggest that the formation of Lewy bodies may be linked to the arrested maturation of α-synuclein condensates in the presence of lipids and other cellular components.

Protective effects of saffron and its constituent crocetin to motor symptoms, short life span and rough-eyed phenotypes in the fly models of Parkinson’s disease in vivo

10.1101/2020.12.06.408997 ◽

2020 ◽

Author(s):

Eiji Inoue ◽

Takahiro Suzuki ◽

Yasuharu Shimizu ◽

Keiichi Sudo ◽

Haruhisa Kawasaki ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Life Span ◽

Neuronal Cell ◽

Crocus Sativus ◽

Motor Symptoms ◽

Protective Effects

AbstractParkinson’s disease (PD) is a common neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the brain. α-Synuclein is an aggregation-prone neural protein that plays a role in the pathogenesis of PD. In our previous paper, we found that saffron; the stigma of Crocus sativus Linné (Iridaceae), and its constituents (crocin and crocetin) suppressed aggregation of α-synuclein and promoted the dissociation of α-synuclein fibrils in vitro. In this study, we investigated the effect of dietary saffron and its constituent, crocetin, in vivo on a fly PD model overexpressing several mutant α-synuclein in a tissue-specific manner. Saffron and crocetin significantly suppressed the decrease of climbing ability in the Drosophila overexpressing A30P (A30P fly PD model) or G51D (G51D fly PD model) mutated α-synuclein in neurons. Saffron and crocetin extended the life span in the G51D fly PD model. Saffron suppressed the rough-eyed phenotype and the dispersion of the size histogram of the ocular long axis in A30P fly PD model in eye. Saffron had a cytoprotective effect on a human neuronal cell line with α-synuclein fibrils. These data showed that saffron and its constituent crocetin have protective effects on the progression of PD disease in animals in vivo and suggest that saffron and crocetin can be used to treat PD.

Potential Role of Caffeine in the Treatment of Parkinson’s Disease

The Open Neurology Journal ◽

10.2174/1874205x01610010042 ◽

2016 ◽

Vol 10 (1) ◽

pp. 42-58 ◽

Cited By ~ 8

Author(s):

Mohsin H.K. Roshan ◽

Amos Tambo ◽

Nikolai P. Pace

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Randomized Clinical Trials ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Muscle Rigidity ◽

Therapeutic Effects ◽

Motor Symptoms ◽

Wide Range

Parkinson’s disease [PD] is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1% of the population over the age of 55. The underlying neuropathology seen in PD is characterised by progressive loss of dopaminergic neurons in the substantia nigra pars compacta with the presence of Lewy bodies. The Lewy bodies are composed of aggregates of α-synuclein. The motor manifestations of PD include a resting tremor, bradykinesia, and muscle rigidity. Currently there is no cure for PD and motor symptoms are treated with a number of drugs including levodopa [L-dopa]. These drugs do not delay progression of the disease and often provide only temporary relief. Their use is often accompanied by severe adverse effects. Emerging evidence from bothin vivoandin vitrostudies suggests that caffeine may reduce parkinsonian motor symptoms by antagonising the adenosine A2Areceptor, which is predominately expressed in the basal ganglia. It is hypothesised that caffeine may increase the excitatory activity in local areas by inhibiting the astrocytic inflammatory processes but evidence remains inconclusive. In addition, the co-administration of caffeine with currently available PD drugs helps to reduce drug tolerance, suggesting that caffeine may be used as an adjuvant in treating PD. In conclusion, caffeine may have a wide range of therapeutic effects which are yet to be explored, and therefore warrants further investigation in randomized clinical trials.