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Molecular Neurobiology Apr 2013The histopathological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is a major... (Review)
Review
The histopathological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is a major constituent. Pale bodies, the precursors of LBs, may serve the material for that LBs continue to expand. LBs consist of a heterogeneous mixture of more than 90 molecules, including PD-linked gene products (α-synuclein, DJ-1, LRRK2, parkin, and PINK-1), mitochondria-related proteins, and molecules implicated in the ubiquitin-proteasome system, autophagy, and aggresome formation. LB formation has been considered to be a marker for neuronal degeneration because neuronal loss is found in the predilection sites for LBs. However, recent studies have indicated that nonfibrillar α-synuclein is cytotoxic and that fibrillar aggregates of α-synuclein (LBs and pale bodies) may represent a cytoprotective mechanism in PD.
Topics: Animals; Humans; Lewy Bodies; Lewy Body Disease; Neurodegenerative Diseases; Parkinson Disease; alpha-Synuclein
PubMed: 22622968
DOI: 10.1007/s12035-012-8280-y -
Nature Protocols Sep 2014This protocol describes a primary neuronal model of formation of α-synuclein (α-syn) aggregates that recapitulate features of the Lewy bodies and Lewy neurites found...
Addition of exogenous α-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous α-synuclein to Lewy body and Lewy neurite-like aggregates.
This protocol describes a primary neuronal model of formation of α-synuclein (α-syn) aggregates that recapitulate features of the Lewy bodies and Lewy neurites found in Parkinson's disease brains and other synucleinopathies. This model allows investigation of aggregate formation, their impact on neuron function, and development of therapeutics. Addition of preformed fibrils (PFFs) synthesized from recombinant α-syn to neurons seeds the recruitment of endogenous α-syn into aggregates characterized by detergent insolubility and hyperphosphorylation. Aggregate formation follows a lag phase of 2-3 d, followed by formation in axons by days 4-7, spread to somatodendritic compartments by days 7-10 and neuron death ~14 d after PFF addition. Here we provide methods and highlight the crucial steps for PFF formation, PFF addition to cultured hippocampal neurons and confirmation of aggregate formation. Neurons derived from various brain regions from nontransgenic and genetically engineered mice and rats can be used, allowing interrogation of the effect of specific genes on aggregate formation.
Topics: Animals; Cell Culture Techniques; Fluorescent Antibody Technique; Immunoblotting; Lewy Bodies; Mice; Models, Biological; Multiprotein Complexes; Neurites; Rats; alpha-Synuclein
PubMed: 25122523
DOI: 10.1038/nprot.2014.143 -
Neuropathology : Official Journal of... Oct 2007The histological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates called Lewy bodies (LBs). LB formation has been considered to be a marker... (Review)
Review
The histological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates called Lewy bodies (LBs). LB formation has been considered to be a marker for neuronal degeneration, because neuronal loss is found in the predilection sites for LBs. To date, more than 70 molecules have been identified in LBs, in which alpha-synuclein is a major constituent of LB fibrils. Alpha-synuclein immunohistochemistry reveals that diffuse cytoplasmic staining develops into pale bodies via compaction, and that LBs arise from the peripheral portion of pale bodies. This alpha-synuclein abnormality is found in 10% of pigmented neurons in the substantia nigra and more than 50% of those in the locus ceruleus in PD. Recent studies have suggested that oligomers and protofibrils of alpha-synuclein are cytotoxic, and that LBs may represent a cytoprotective mechanism in PD.
Topics: Brain Stem; Cerebral Cortex; Enzymes; Humans; Lewy Bodies; Nerve Tissue Proteins; Parkinson Disease; alpha-Synuclein
PubMed: 18018486
DOI: 10.1111/j.1440-1789.2007.00803.x -
Current Opinion in Neurology and... Dec 1992Subsumed under the rubric of Lewy body disease are idiopathic Parkinson's disease (PD), pure diffuse Lewy body disease (DLBD), and, most commonly, combined brainstem and... (Review)
Review
Subsumed under the rubric of Lewy body disease are idiopathic Parkinson's disease (PD), pure diffuse Lewy body disease (DLBD), and, most commonly, combined brainstem and neocortical Lewy bodies with Alzheimer's disease (AD) pathology in a relatively early developmental stage. Clinical correlates are dementia with psychiatric and subcortical features plus mild extrapyramidal signs (EPS).
Topics: Alzheimer Disease; Brain; Diagnosis, Differential; Humans; Lewy Bodies; Microscopy, Electron; Neurofibrillary Tangles; Neurologic Examination; Parkinson Disease
PubMed: 1467583
DOI: No ID Found -
Annals of Neurology Jan 2023The objective of this study was to evaluate the relationship between Parkinson's disease (PD) with dementia and cortical proteinopathies in a large population of... (Review)
Review
OBJECTIVE
The objective of this study was to evaluate the relationship between Parkinson's disease (PD) with dementia and cortical proteinopathies in a large population of pathologically confirmed patients with PD.
METHODS
We reviewed clinical data from all patients with autopsy data seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2019. All patients with a diagnosis of PD based on neuropathology were included. We used logistic regression and multivariate analysis of covariance (MANCOVA) to investigate the relationship between neuropathology and dementia.
RESULTS
A total of 165 patients with PD met inclusion criteria. Among these, 128 had clinical dementia. Those with dementia had greater mean ages of motor onset and death but equivalent mean disease duration. The delay between motor symptom onset and dementia was 1 year or less in 14 individuals, meeting research diagnostic criteria for possible or probable dementia with Lewy bodies (DLB). Braak Lewy body stage was associated with diagnosis of dementia, whereas severities of Alzheimer's disease neuropathologic change (ADNC) and small vessel pathology did not. Pathology of individuals diagnosed with DLB did not differ significantly from that of other patients with PD with dementia. Six percent of individuals with PD and dementia did not have neocortical Lewy bodies; and 68% of the individuals with PD but without dementia did have neocortical Lewy bodies.
INTERPRETATION
Neocortical Lewy bodies almost always accompany dementia in PD; however, they also appear in most PD patients without dementia. In some cases, dementia may occur in patients with PD without neocortical Lewy bodies, ADNC, or small vessel disease. Thus, other factors not directly related to these classic neuropathologic features may contribute to PD dementia. ANN NEUROL 2023;93:184-195.
Topics: Humans; Lewy Bodies; Parkinson Disease; Lewy Body Disease; Neocortex; Alzheimer Disease
PubMed: 36331161
DOI: 10.1002/ana.26542 -
Molecular Neurodegeneration May 2023Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is... (Review)
Review
BACKGROUND
Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is currently no disease-modifying treatment to halt neuronal loss in PD. A major hurdle for developing and testing such curative therapies results from the fact that most DA neurons are already lost at the time of the clinical diagnosis, rendering them inaccessible to therapy. Understanding the early pathological changes that precede Lewy body pathology (LBP) and cell loss in PD will likely support the identification of novel diagnostic and therapeutic strategies and help to differentiate LBP-dependent and -independent alterations. Several previous studies identified such specific molecular and cellular changes that occur prior to the appearance of Lewy bodies (LBs) in DA neurons, but a concise map of such early disease events is currently missing.
METHODS
Here, we conducted a literature review to identify and discuss the results of previous studies that investigated cases with incidental Lewy body disease (iLBD), a presumed pathological precursor of PD.
RESULTS
Collectively, our review demonstrates numerous cellular and molecular neuropathological changes occurring prior to the appearance of LBs in DA neurons.
CONCLUSIONS
Our review provides the reader with a summary of early pathological events in PD that may support the identification of novel therapeutic and diagnostic targets and aid to the development of disease-modifying strategies in PD.
Topics: Humans; Parkinson Disease; Lewy Bodies; Lewy Body Disease; Nerve Degeneration; Neuropathology; alpha-Synuclein
PubMed: 37173733
DOI: 10.1186/s13024-023-00622-7 -
Neurobiology of Disease Nov 2023Dementia with Lewy bodies and Parkinson's disease dementia are common neurodegenerative diseases that share similar neuropathological profiles and spectra of clinical... (Review)
Review
Dementia with Lewy bodies and Parkinson's disease dementia are common neurodegenerative diseases that share similar neuropathological profiles and spectra of clinical symptoms but are primarily differentiated by the order in which symptoms manifest. The question of whether a distinct molecular pathological profile could distinguish these disorders is yet to be answered. However, in recent years, studies have begun to investigate genomic, epigenomic, transcriptomic and proteomic differences that may differentiate these disorders, providing novel insights in to disease etiology. In this review, we present an overview of the clinical and pathological hallmarks of Lewy body dementias before summarizing relevant research into genetic, epigenetic, transcriptional and protein signatures in these diseases, with a particular interest in those resolving "omic" level changes. We conclude by suggesting future research directions to address current gaps and questions present within the field.
Topics: Humans; Lewy Body Disease; Dementia; Parkinson Disease; Proteomics; Lewy Bodies
PubMed: 37918758
DOI: 10.1016/j.nbd.2023.106337 -
Annals of Medicine Jun 1999Although Lewy body dementia (LBD) has received a considerable amount of interest in the last decade, there still exists a certain level of confusion concerning the... (Review)
Review
Although Lewy body dementia (LBD) has received a considerable amount of interest in the last decade, there still exists a certain level of confusion concerning the clinical and neuropathological features associated with this disorder. According to many researchers, LBD represents a distinct dementing illness with specific clinical features. The neuropathological hallmark for this disorder is the Lewy body, a spherical intraneuronal cytoplasmic inclusion originally described in brainstem nuclei in Parkinson's disease. In LBD, Lewy bodies are found in subcortical nuclei, such as the substantia nigra, as well as diffusely in the neocortex. Recently, a consortium on dementia with Lewy bodies was held that established consensus guidelines for the clinical and pathological diagnosis of LBD. This review will focus on the newest developments in LBD, addressing specifically clinical and neuropathological features, diagnostic classification, genetics and potential pharmacotherapy.
Topics: Diagnosis, Differential; Female; Humans; Levodopa; Lewy Bodies; Male; Parkinson Disease; Prevalence
PubMed: 10442673
DOI: 10.3109/07853899909115977 -
Proceedings of the National Academy of... Mar 2020Parkinson's disease (PD) is characterized by the accumulation of misfolded and aggregated α-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LBs)....
Parkinson's disease (PD) is characterized by the accumulation of misfolded and aggregated α-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LBs). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD, the processes that govern α-syn fibrillization and LB formation remain poorly understood. In this work, we sought to dissect the spatiotemporal events involved in the biogenesis of the LBs at the genetic, molecular, biochemical, structural, and cellular levels. Toward this goal, we further developed a seeding-based model of α-syn fibrillization to generate a neuronal model that reproduces the key events leading to LB formation, including seeding, fibrillization, and the formation of inclusions that recapitulate many of the biochemical, structural, and organizational features of bona fide LBs. Using an integrative omics, biochemical and imaging approach, we dissected the molecular events associated with the different stages of LB formation and their contribution to neuronal dysfunction and degeneration. In addition, we demonstrate that LB formation involves a complex interplay between α-syn fibrillization, posttranslational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria, the autophagosome, and endolysosome. Finally, we show that the process of LB formation, rather than simply fibril formation, is one of the major drivers of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, and synaptic dysfunctions. We believe that this model represents a powerful platform to further investigate the mechanisms of LB formation and clearance and to screen and evaluate therapeutics targeting α-syn aggregation and LB formation.
Topics: Animals; Autophagosomes; Humans; Lewy Bodies; Lysosomes; Mitochondria; Neurodegenerative Diseases; Neurons; Parkinson Disease; Transcriptome; alpha-Synuclein
PubMed: 32075919
DOI: 10.1073/pnas.1913904117 -
Neuropathology : Official Journal of... Feb 2020Lewy body disease (LBD) is characterized by the presence of Lewy bodies (LBs) and Lewy neurites and comprises a diagnostic spectrum that includes Parkinson's disease... (Review)
Review
Lewy body disease (LBD) is characterized by the presence of Lewy bodies (LBs) and Lewy neurites and comprises a diagnostic spectrum that includes Parkinson's disease (PD), PD with dementia, and dementia with LBs. LBs and Lewy neurites are insoluble aggregates composed mainly of phosphorylated α-synuclein and can be widely distributed throughout the central and peripheral nervous systems. The distribution of LBs may determine the LBD phenotype. Braak hypothesized that Lewy pathology progresses ascendingly from the peripheral nervous system to the olfactory bulbs and brainstem and then to other brain regions. Braak's PD staging suggests that LBD is a prion-like disease. Most typical PD cases fit with Braak's PD staging, but the scheme fails in some cases. Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, frontotemporal lobar degeneration, Creutzfeldt-Jakob disease, cerebrovascular diseases, and essential tremor are common misdiagnoses for pathologically confirmed LBD. LBD exhibits considerable heterogeneity in both clinical and pathological settings, which makes clinical diagnosis challenging.
Topics: Brain; Humans; Lewy Bodies; Lewy Body Disease; Macrophages; Neuropathology; alpha-Synuclein
PubMed: 31498507
DOI: 10.1111/neup.12597