Appearance Of Lewy Bodies Research Articles

High-content phenotyping of Parkinson's disease patient stem cell-derived midbrain dopaminergic neurons using machine learning classification.

SummaryCombining multiple Parkinson's disease (PD) relevant cellular phenotypes might increase the accuracy of midbrain dopaminergic neuron (mDAN) in vitro models. We differentiated patient-derived induced pluripotent stem cells (iPSCs) with a LRRK2 G2019S mutation, isogenic control, and genetically unrelated iPSCs into mDANs. Using automated fluorescence microscopy in 384-well-plate format, we identified elevated levels of α-synuclein (αSyn) and serine 129 phosphorylation, reduced dendritic complexity, and mitochondrial dysfunction. Next, we measured additional image-based phenotypes and used machine learning (ML) to accurately classify mDANs according to their genotype. Additionally, we show that chemical compound treatments, targeting LRRK2 kinase activity or αSyn levels, are detectable when using ML classification based on multiple image-based phenotypes. We validated our approach using a second isogenic patient-derived SNCA gene triplication mDAN model which overexpresses αSyn. This phenotyping and classification strategy improves the practical exploitability of mDANs for disease modeling and the identification of novel LRRK2-associated drug targets.

Impact of Environmental Risk Factors on Mitochondrial Dysfunction, Neuroinflammation, Protein Misfolding, and Oxidative Stress in the Etiopathogenesis of Parkinson's Disease.

As a prevalent progressive neurodegenerative disorder, Parkinson’s disease (PD) is characterized by the neuropathological hallmark of the loss of nigrostriatal dopaminergic (DAergic) innervation and the appearance of Lewy bodies with aggregated α-synuclein. Although several familial forms of PD have been reported to be associated with several gene variants, most cases in nature are sporadic, triggered by a complex interplay of genetic and environmental risk factors. Numerous epidemiological studies during the past two decades have shown positive associations between PD and several environmental factors, including exposure to neurotoxic pesticides/herbicides and heavy metals as well as traumatic brain injury. Other environmental factors that have been implicated as potential risk factors for PD include industrial chemicals, wood pulp mills, farming, well-water consumption, and rural residence. In this review, we summarize the environmental toxicology of PD with the focus on the elaboration of chemical toxicity and the underlying pathogenic mechanisms associated with exposure to several neurotoxic chemicals, specifically 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, paraquat (PQ), dichloro-diphenyl-trichloroethane (DDT), dieldrin, manganese (Mn), and vanadium (V). Our overview of the current findings from cellular, animal, and human studies of PD provides information for possible intervention strategies aimed at halting the initiation and exacerbation of environmentally linked PD.

Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Familial Parkinson's Disease Patients Display α-Synuclein Pathology and Abnormal Mitochondrial Morphology.

Accumulation of α-synuclein (α-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson’s disease (PD), which are associated with the loss of dopaminergic neurons. Although α-syn accumulates in many different cellular and mouse models, these models generally lack LB features. Here, we generated midbrain dopaminergic (mDA) neuronal cultures from induced pluripotent stem cells (iPSCs) derived from familial PD (fPD) patients and healthy controls. We show that mDA neuronal cultures from fPD patients with A53T mutation and α-syn gene (SNCA) triplication display pathological α-syn deposits, which spatially and morphologically resemble LBs. Importantly, we did not find any apparent accumulation of pathological α-syn in mDA neuronal culture derived from a healthy donor. Furthermore, we show that there are morphological abnormalities in the mitochondrial network in mDA neuronal cultures from fPD patients. Consequently, these cells were more susceptible to mitochondrial damage compared with healthy donor-derived mDA neuronal cultures. Our results indicate that the iPSC-derived mDA neuronal culture platform can be used to investigate the spatiotemporal appearance of LBs, as well as their composition, architecture, and relationship with mitochondrial abnormalities.

Emerging Nondopaminergic Medications for Parkinson's Disease: Focusing on A2A Receptor Antagonists and GLP1 Receptor Agonists.

Parkinson’s disease (PD) is a severe neurodegenerative disease characterized by classic motor features associated with the loss of dopaminergic neurons and appearance of Lewy bodies in the substantia nigra. Due to the complexity of PD, a definitive diagnosis in the early stages and effective management of symptoms in later stages are difficult to achieve in clinical practice. Previous research has shown that colocalization of A2A receptors (A2AR) and dopamine D2 receptors (D2R) may induce an antagonistic interaction between adenosine and dopamine. Clinical trials have found that the A2AR antagonist istradefylline decreases dyskinesia in PD and could be used as an adjuvant to levodopa treatment. Meanwhile, the incretin hormone glucagon-like peptide 1 (GLP1) mainly facilitates glucose homeostasis and insulin signaling. Preclinical experiments and clinical trials of GLP1 receptor (GLP1R) agonists show that they may be effective in alleviating neuroinflammation and sustaining cellular functions in the central nervous system of patients with PD. In this review, we summarize up-to-date findings on the usefulness of A2AR antagonists and GLP1R agonists in PD management. We explain the molecular mechanisms of these medications and their interactions with other neurotransmitter receptors. Furthermore, we discuss the efficacy and limitations of A2AR antagonists and GLP1R agonists in clinical practice.

Neuroinflammation in Parkinson´s Disease: role of cholesterol

Neuroinflammation in Parkinson´s Disease: role of cholesterol

The Role of Cholesterol in α-Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease.

ABSTRACTParkinson's disease (PD) is a progressive neurodegenerative disease where dopaminergic neurons in the substantia nigra are lost, resulting in a decrease in striatal dopamine and, consequently, motor control. Dopaminergic degeneration is associated with the appearance of Lewy bodies, which contain membrane structures and proteins, including α‐synuclein (α‐Syn), in surviving neurons. PD displays a multifactorial pathology and develops from interactions between multiple elements, such as age, environmental conditions, and genetics. Mutations in the GBA1 gene represent one of the major genetic risk factors for PD. This gene encodes an essential lysosomal enzyme called β‐glucocerebrosidase (GCase), which is responsible for degrading the glycolipid glucocerebroside into glucose and ceramide. GCase can generate glucosylated cholesterol via transglucosylation and can also degrade the sterol glucoside. Although the molecular mechanisms that predispose an individual to neurodegeneration remain unknown, the role of cholesterol in PD pathology deserves consideration. Disturbed cellular cholesterol metabolism, as reflected by accumulation of lysosomal cholesterol in GBA1‐associated PD cellular models, could contribute to changes in lipid rafts, which are necessary for synaptic localization and vesicle cycling and modulation of synaptic integrity. α‐Syn has been implicated in the regulation of neuronal cholesterol, and cholesterol facilitates interactions between α‐Syn oligomers. In this review, we integrate the results of previous studies and describe the cholesterol landscape in cellular homeostasis and neuronal function. We discuss its implication in α‐Syn and Lewy body pathophysiological mechanisms underlying PD, focusing on the role of GCase and cholesterol. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Microglia and Parkinson's disease: footprints to pathology.

Parkinson's disease (PD) is a neurodegenerative disease associated with motor deficiency and rigidity. The genetic risks of the disease is reported to be between 5 and 10% depending on the background of the population. While PD is not considered an immune-mediated disease, amounting evidence in recent years suggests a major role of inflammation in the progression of PD. Markers of inflammation can be found around the regions of risk and adjacent to the appearance of Lewy bodies within the basal ganglia and the substantia nigra (SN) that are associated with PD pathology. Microglia, an important type of brain cell, has been reported to play a major role in mediating neuroinflammation and in PD disease pathology. This review aims to point out the potential role of microglia in disease progression and suggest that the interaction of microglia with the dopaminergic neurons may also facilitate the specificity of the disease in brain regions affected by PD.

Pathophysiology and management of parkinson disease: a review

Parkinson’s disease is a neurological disorder that is characterized by the typical motor symptoms of Parkinsonism associated with Lewy bodies and loss of dopaminergic neurons within the substantia nigra. It is associated with fluctuations of motor and non-motor symptoms, dyskinesia and psychosis. Parkinson’s disease affects almost 1% of individuals older than 60 years. The incidence is higher in Europe, North and South America compared to Africa. Male to female ratio is 3:2. The aim of this review is to describe the pathophysiology and management of Parkinson’s disease. Aetiological risk factors of Parkinson’s disease were theorised to be due to genetic and environmental factors. Some of the environmental risk factors include chronic pesticide exposure, prior head injury etc. while some of the genetic risk factors include beta-glucocerobrosidase gene (GBA), leucine- rich repeat kinase-2 (LRRK2) and synuclein alpha (SNCA) genes. Parkinson disease is mainly a disorder of the basal ganglia, a group of nuclei located at the base of the forebrain. There are two main neuropathological discoveries related to the disease: the damage of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNpc), and the appearance of Lewy bodies that leads to the formation of Lewy neurites, which are typical pathologic outcomes in Parkinson disease. The management comprises of diagnosis and treatment. The diagnosis is mainly clinical while the treatment is essentially medical which include. Levodopa/carbidopa administration in combination for control of motor symptoms.Keywords; Parkinson’s disease, Substantia nigra, Lewy bodies, levodopa, dopaminergicneurons.

Lewy body constipation.

We systematically reviewed literature regarding “Lewy body constipation”, i.e., constipation due to Lewy body diseases (LBD), with minimal neurologic symptoms. Epidemiology and pathology studies showed that LBD can start with constipation alone, mostly due to neuronal loss and appearance of Lewy bodies in the myenteric plexus. Because LBD significantly increases with age, “Lewy body constipation” may also increase with age. Neuroimaging methods such as metaiodobenzylguanidine (MIBG) scintigraphy and dopamine transporter (DAT) scan provide a way to detect “Lewy body constipation.” Key for “Lewy body constipation” includes minimal non-motor features such as REM sleep behavior disorder (night talking). Add-on therapy may be required to ameliorate constipation in patients. Diagnosis is not always easy; therefore, collaboration of gastroenterologists and neurologists is highly recommended to maximize patients' quality of life. In conclusion, “Lewy body constipation” might become a distinct category among geriatric constipation, regarding patients' follow-up and their management.

Do Th17 Lymphocytes and IL-17 Contribute to Parkinson's Disease? A Systematic Review of Available Evidence.

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic neurons, appearance of Lewy bodies and presence of neuroinflammation. No treatments currently exist to prevent PD or delay its progression, and dopaminergic substitution treatments just relieve the consequences of dopaminergic neuron loss. Increasing evidence points to peripheral T lymphocytes as key players in PD, and recently there has been growing interest into the specific role of T helper (Th) 17 lymphocytes. Th17 are a proinflammatory CD4+ T cell lineage named after interleukin (IL)-17, the main cytokine produced by these cells. Th17 are involved in immune-related disease such as psoriasis, rheumatoid arthritis and inflammatory bowel disease, and drugs targeting Th17/IL-17 are currently approved for clinical use in such disease. In the present paper, we first summarized current knowledge about contribution of the peripheral immune system in PD, as well as about the physiopharmacology of Th17 and IL-17 together with its therapeutic relevance. Thereafter, we systematically retrieved and evaluated published evidence about Th17 and IL-17 in PD, to help assessing Th17/IL-17-targeting drugs as potentially novel antiparkinson agents. Critical appraisal of the evidence did not allow to reach definite conclusions: both animal as well as clinical studies are limited, just a few provide mechanistic evidence and none of them investigates the eventual relationship between Th17/IL-17 and clinically relevant endpoints such as disease progression, disability scores, intensity of dopaminergic substitution treatment. Careful assessment of Th17 in PD is anyway a priority, as Th17/IL-17-targeting therapeutics might represent a straightforward opportunity for the unmet needs of PD patients.

α-Synucleinopathy in the Human Amygdala in Parkinson Disease: Differential Vulnerability of Somatostatin- and Parvalbumin-Expressing Neurons.

Olfactory dysfunction and emotional impairment are nonmotor symptoms in Parkinson disease (PD). These symptoms might be correlated with the appearance of Lewy bodies and neurites (ubiquitin and α-synuclein aggregates) in the amygdala (Braak stage 3). α-Synucleinopathy in the amygdala has been studied only occasionally, and no data on cell types involved are available. This work aimed to analyze α-synuclein expression in the basolateral, central, and cortical amygdaloid nuclei in 5 PD patients (Braak stages 3-5) and 5 controls. Expression of somatostatin and parvalbumin as well as its colocalization with α-synuclein was quantified under confocal microscopy. α-synuclein expression did not differ significantly between the central and other nuclei. The density of somatostatin was significantly decreased in the basolateral and central complex. The density of parvalbumin was significantly diminished in the basolateral complex. Parvalbumin-positive cells colocalized frequently with α-synuclein (68.44%), whereas, somatostatin-positive cells colocalized only occasionally (6.98%). These data revealed the differential vulnerability among interneuron populations in the human amygdala and could help to explain nonmotor symptoms such as anhedonia in PD.

Toxic Dopamine Metabolite DOPAL Forms an Unexpected Dicatechol Pyrrole Adduct with Lysines of α‐Synuclein

AbstractParkinson's disease has long been known to involve the loss of dopaminergic neurons in the substantia nigra and the coincidental appearance of Lewy bodies containing oligomerized forms of α‐synuclein. The “catecholaldehyde hypothesis” posits a causal link between these two central pathologies mediated by 3,4‐dihydroxyphenylacetaldehyde (DOPAL), the most toxic dopamine metabolite. Here we determine the structure of the dominant product in reactions between DOPAL and α‐synuclein, a dicatechol pyrrole lysine adduct. This novel modification results from the addition of two DOPAL molecules to the Lys sidechain amine through their aldehyde moieties and the formation of a new carbon–carbon bond between their alkyl chains to generate a pyrrole ring. The product is detectable at low concentrations of DOPAL and its discovery should provide a valuable chemical basis for future studies of DOPAL‐induced crosslinking of α‐synuclein.

Toxic Dopamine Metabolite DOPAL Forms an Unexpected Dicatechol Pyrrole Adduct with Lysines of α-Synuclein.

Parkinson's disease has long been known to involve the loss of dopaminergic neurons in the substantia nigra and the coincidental appearance of Lewy bodies containing oligomerized forms of α-synuclein. The "catecholaldehyde hypothesis" posits a causal link between these two central pathologies mediated by 3,4-dihydroxyphenylacetaldehyde (DOPAL), the most toxic dopamine metabolite. Here we determine the structure of the dominant product in reactions between DOPAL and α-synuclein, a dicatechol pyrrole lysine adduct. This novel modification results from the addition of two DOPAL molecules to the Lys sidechain amine through their aldehyde moieties and the formation of a new carbon-carbon bond between their alkyl chains to generate a pyrrole ring. The product is detectable at low concentrations of DOPAL and its discovery should provide a valuable chemical basis for future studies of DOPAL-induced crosslinking of α-synuclein.

New insights on Parkinson's disease genes: the link between mitochondria impairment and neuroinflammation.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor disturbances, appearance of Lewy bodies and dopaminergic neuronal death. The etiology of PD is unknown, although aging and neurotoxins are established risk factors. The activation of glial cells in the brain is the first defense mechanism against pathological events in neurodegenerative diseases, and neuroinflammation is suggested to play an important role in PD disease progression leading to dopaminergic neuronal degeneration. Gene mutations in several PD-related genes may affect up to 15% of the PD cases. These gene mutations can cause either loss or gain of function in their respective proteins leading to autosomal recessive and autosomal dominant PD, respectively. Most of the identified genes play a role in mitochondrial activity and integrity, and this was demonstrated mostly in neuronal cells. In this review, we aim to describe the link between PD-related genes, which are involved in mitochondrial function, and deleterious neuroinflammation.

New α- and γ-synuclein immunopathological lesions in human brain.

IntroductionSeveral neurodegenerative diseases are classified as proteopathies as they are associated with the aggregation of misfolded proteins. Synucleinopathies are a group of neurodegenerative disorders associated with abnormal deposition of synucleins. α-Synucleinopathies include Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Recently accumulation of another member of the synuclein family- γ−synuclein in neurodegenerative diseases compelled the introduction of the term γ−synucleinopathy. The formation of aggregates and deposits of γ−synuclein is facilitated after its oxidation at methionine 38 (Met38).ResultsSeveral types of intracytoplasmic inclusions containing post-translationally modified α- and γ−synucleins are detected. Oxidized Met38-γ-synuclein forms aberrant inclusions in amygdala and substantia nigra. Double staining revealed colocalization of oxidized-γ-synuclein with α-synuclein in the cytoplasm of neurons. Another type of synuclein positive inclusions in the amygdala of dementia with Lewy bodies patients has the appearance of Lewy bodies. These inclusions are immunoreactive when analyzed with antibodies to α-synuclein phosphorylated on serine 129, as well as with antibodies to oxidized-γ-synuclein. Some of these Lewy bodies have doughnut-like shape with round or elongated shape. The separate immunofluorescent images obtained with individual antibodies specific to oxidized-γ-synuclein and phospho-α-synuclein clearly shows the colocalization of these synuclein isoforms in substantia nigra inclusions. Phospho-α-synuclein is present almost exclusively at the periphery of these structures, whereas oxidized-γ-syn immunoreactivity is also located in the internal parts forming dot-like pattern of staining.We also identified several types of oxidized-γ-syn positive astrocytes with different morphology and examined their immunohistochemical phenotypes. Some of them are compact cells with short processes, others have longer processes. Oxidized-γ-synuclein positive astrocytes may also display mixed morphological and immunocytochemical phenotypes between protoplasmic and fibrous astrocytes.ConclusionsThese results reveal new γ−synuclein positive lesions in human brain. Oxidized-γ-synuclein is colocalized with phospho-α-synuclein in doughnut-like inclusions. Several types of astrocytes with different morphology are immunopositive for oxidized-γ-synuclein.

A phenotypic model recapitulating the neuropathology of Parkinson's disease

This study was undertaken to develop a phenotypic model recapitulating the neuropathology of Parkinson's disease (PD). Such a model would show loss of dopamine in the basal ganglia, appearance of Lewy bodies, and the early stages of motor dysfunction. The model was developed by subcutaneously injecting biodegradable microspheres of rotenone, a complex I inhibitor in 8–9 month old, ovariectomized Long–Evans rats. Animals were observed for changes in body weight and motor activity. At the end of 11–12 weeks animals were euthanized and the brains examined for histopathological changes. Rotenone treated animals gain weight and appear normal and healthy as compared to controls but showed modest hypokinesia around 5–6 weeks posttreatment. Animals showed loss of dopaminergic (DA) neurons and the appearance of putative Lewy bodies in the substantia nigra. Neuroinflammation and oxidative stress were evidenced by the appearance of activated microglia, iron precipitates, and 8-oxo-2′-deoxyguanosine a major product of DNA oxidation. The dorsal striatum, the projection site of midbrain DA neurons, showed a significant reduction in tyrosine hydroxylase immunostaining, together with an increase in reactive astrocytes, an early sign of DA nerve terminal damage. Levels of vesicular monoamine transporter 2 (VMAT2) were significantly reduced in the dorsal striatum; however, there was an unexpected increase in dopamine transporter (DAT) levels. Old, ovariectomized females treated with rotenone microspheres present with normal weight gain and good health but a modest hypokinesia. Accompanying this behavioral phenotype are a constellation of neuropathologies characteristic of PD that include loss of DA neurons, microglia activation, oxidative damage to nuclear DNA, iron deposition, and appearance of putative Lewy bodies. This phenotypic model recapitulating the neuropathology of Parkinson's disease could provide insight into early mechanisms of pathogenesis and could aid in the identification of biomarkers to identify patients in early stage, PD.

Evaluation of the Braak staging scheme for Parkinson's disease: Introduction to a panel presentation

Braak and colleagues have proposed a staging scheme for Parkinson's disease (PD) based on patterns of abnormal immunostaining for alpha-synuclein. They have proposed a temporal sequence in which the appearance of Lewy bodies and neurites in brainstem structures represent the earliest manifestations of the disease, and that this involvement of non-dopaminergic structures long antedates involvement of the substantia nigra and the appearance of the cardinal motor signs that are now required for diagnosis. This proposed scheme has had a wide and profound impact on many aspects of current thinking about PD, and it has already received wide acceptance. Given the importance and growing acceptance of the Braak staging scheme, the Scientific Program Committee for this Educational Symposium to honor the 50th Anniversary of the Parkinson's Disease Foundation agreed that it would be highly worthwhile to devote an entire session of the Scientific Program to consideration of the Braak staging scheme. There was a consensus among members of the Committee that, given the importance of the Braak scheme, it would be of value to create a venue that would stimulate and encourage a thorough and incisive critical analysis.

Dopamine facilitates α-synuclein oligomerization in human neuroblastoma SH-SY5Y cells

Parkinson’s disease is characterized by selective loss of dopaminergic neurons in the substantia nigra and by the appearance of Lewy bodies. Fibrillar α-synuclein is the main component of Lewy bodies. Previous studies have suggested that dopamine promotes α-synuclein oligomerization and that partially aggregated or oligomeric α-synuclein could be cytotoxic. To confirm this hypothesis using cell cultures, we performed size exclusion chromatography as a pretreatment method prior to Western blotting to more clearly detect a small amount of α-synuclein oligomers in wild-type α-synuclein-overexpressing SH-SY5Y cells. Using this method, we confirmed that stable overexpression of α-synuclein in SH-SY5Y cells indeed increased the amounts of α-synuclein oligomers in these cells and exposure of the cells to dopamine for 6h facilitated α-synuclein oligomerization. These dopamine-induced α-synuclein oligomers continued to exist for the following 24h. However, the dopamine-treated cells did not undergo cell death or apoptosis in spite of the presence of increased oligomeric α-synuclein. Our data may contribute to the understanding of the mechanisms underlying α-synuclein oligomer formation and its suspected cytotoxicity toward dopaminergic neurons.

Parkinson's disease: Genetic aspects and insights into physiopathology

Event Abstract Back to Event Parkinson's disease: Genetic aspects and insights into physiopathology Alexis Brice1* 1 / UPMC Université Paris 06, UMR_S679, F-75005, Paris, France / 3AP-HP, Hôpital de la Salpêtrière, Service, INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, Paris, France, France Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder, characterized clinically by motor symptoms and pathologically by the selective loss of dopaminergic neurons in the substantia nigra and the appearance of Lewy bodies in surviving neurons. Although the etiology of PD remains elusive, the identification of rare monogenic forms in 5 – 10 % of PD patients has provided crucial insights into molecular mechanisms in disease pathogenesis. At least 13 loci and 9 genes have been identified to date. Mutations in the α-synuclein gene in rare families with autosomal dominant PD indicate that aggregation of this protein in Lewy bodies plays a crucial role in the pathogenesis of this disorder. Mutations in the leucine-rich repeat kinase 2 (LRRK2) have been identified as a much more frequent cause of autosomal dominant PD. Loss-of-function mutations in the parkin, PINK1 and DJ-1 cause autosomal recessive parkinsonism with early-onset. Their role in the proteasomal protein degradation pathway, the oxidative stress response and mitochondrial function shed light in understanding the convergent pathways leading to neurodegeneration. Keywords: autosomal dominant forms, autosomal recessive forms, Parkinson's disease Conference: 3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009. Presentation Type: Oral Presentation Topic: Plenary lectures Citation: Brice A (2009). Parkinson's disease: Genetic aspects and insights into physiopathology. Front. Neurosci. Conference Abstract: 3rd Mediterranean Conference of Neuroscience . doi: 10.3389/conf.neuro.01.2009.16.012 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 18 Nov 2009; Published Online: 18 Nov 2009. * Correspondence: Alexis Brice, / UPMC Université Paris 06, UMR_S679, F-75005, Paris, France / 3AP-HP, Hôpital de la Salpêtrière, Service, INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, Paris, France, F-75013, Paris, France, alexis.brice@upmc.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Alexis Brice Google Alexis Brice Google Scholar Alexis Brice PubMed Alexis Brice Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Value of genetic models in understanding the cause and mechanisms of Parkinson’s disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the degeneration of nigrostriatal pathway dopaminergic neurons and other neuronal systems and the appearance of Lewy bodies that contain alpha-synuclein. PD is generally a sporadic disease, but a small proportion of cases have a clear genetic component. Mutations have been identified in six genes that clearly segregate with disease in rare families with PD. Transgenic, knockout, and virus-based models of disease have been developed in rodents to further understand how these genes contribute to the pathogenesis of PD. In general, these animal models recapitulate many key features of the disease, including derangements in dopaminergic synaptic transmission, selective neurodegeneration, neurochemical deficits, alpha-synuclein-positive neuropathology, and motor deficits. However, a genetic model with all or most of these pathogenic features has proved difficult to create. In this article, we discuss these mammalian genetic models of PD and what they have revealed about the cause and mechanisms of this disease.