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Biochimica Et Biophysica Acta.... Apr 2021Parkinson's disease is an increasingly prevalent and currently incurable neurodegenerative disorder. At the molecular level, this disease is characterized by the... (Review)
Review
Parkinson's disease is an increasingly prevalent and currently incurable neurodegenerative disorder. At the molecular level, this disease is characterized by the formation of aberrant intracellular protein deposits known as Lewy bodies. Oligomeric forms of the protein α-synuclein (αS), which are believed to be both intermediates and by-products of Lewy body formation, are considered to be the main pathogenic species. Interactions of such oligomers with lipid membranes are increasingly emerging as a major molecular pathway underpinning their toxicity. Here we review recent progress in our understanding of the interactions of αS oligomers with lipid membranes. We highlight key structural and biophysical features of αS oligomers, the effects of these features on αS oligomer membrane binding properties, and resultant implications for understanding the etiology of Parkinson's disease. We discuss mechanistic modes of αS oligomer-lipid membrane interactions and the effects of environmental factors to such modes. Finally, we provide an overview of the current understanding of the main molecular determinants of αS oligomer toxicity in vivo.
Topics: Animals; Cell Membrane; Humans; Lewy Bodies; Parkinson Disease; Protein Multimerization; alpha-Synuclein
PubMed: 33373595
DOI: 10.1016/j.bbamem.2020.183536 -
Neurobiology of Disease Jun 2022Dementia with Lewy bodies (DLB) is the second most common neurodegenerative cause of dementia, behind Alzheimer's disease (AD). The profile of inflammation in AD has... (Review)
Review
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative cause of dementia, behind Alzheimer's disease (AD). The profile of inflammation in AD has been extensively researched in recent years, with evidence that chronic peripheral inflammation in midlife increases the risk of late-onset AD, and data supporting inflammation being associated with disease progression. In contrast, our understanding of the role of inflammation in DLB is less developed. Most research to date has examined inflammation in related disorders, such as Parkinson's disease, but there is now a growing range of literature examining inflammation in DLB itself. We present a review of the literature in this field, exploring a range of research methodologies including those quantifying markers of inflammation in cerebrospinal fluid, peripheral blood, post-mortem brain tissue, and using neuroimaging and preclinical data. Our review reveals evidence from PET imaging and peripheral blood analysis to support an increase in cerebral and peripheral inflammation in mild or prodromal DLB, that dissipates with disease progression. We present evidence from post-mortem brain tissue and pre-clinical studies that indicate α-synuclein directly promotes inflammation, but that also support the presence of AD co-pathology as an important factor in the profile of neuroinflammation in DLB. We propose that specific markers of inflammation may play a sentinel role in the mild stage of the disease, particularly when combined with AD pathology. We advocate further examination of the profile of inflammation in DLB through robust longitudinal studies, to enhance our understanding of the pathogenesis of the disease. The goal should be to utilise future results to develop a composite biomarker to aid diagnosis of DLB, and to potentially identify novel therapeutic targets.
Topics: Alzheimer Disease; Biomarkers; Disease Progression; Humans; Inflammation; Lewy Bodies; Lewy Body Disease
PubMed: 35314318
DOI: 10.1016/j.nbd.2022.105698 -
Nature Medicine Aug 2023α-Synuclein aggregates constitute the pathology of Lewy body (LB) disease. Little is known about the effects of LB pathology in preclinical (presymptomatic)...
α-Synuclein aggregates constitute the pathology of Lewy body (LB) disease. Little is known about the effects of LB pathology in preclinical (presymptomatic) individuals, either as isolated pathology or coexisting with Alzheimer's disease (AD) pathology (β-amyloid (Aβ) and tau). We examined the effects of LB pathology using a cerebrospinal fluid α-synuclein-seed amplification assay in 1,182 cognitively and neurologically unimpaired participants from the BioFINDER study: 8% were LB positive, 26% Aβ positive (13% of those were LB positive) and 16% tau positive. LB positivity occurred more often in the presence of Aβ positivity but not tau positivity. LB pathology had independently negative effects on cross-sectional and longitudinal global cognition and memory and on longitudinal attention/executive function. Tau had cognitive effects of a similar magnitude, but these were less pronounced for Aβ. Participants with both LB and AD (Aβ and tau) pathology exhibited faster cognitive decline than those with only LB or AD pathology. LB, but not AD, pathology was associated with reduced sense of smell. Only LB-positive participants progressed to clinical LB disease over 10 years. These results are important for individualized prognosis, recruitment and choice of outcome measures in preclinical LB disease trials, but also for the design of early AD trials because >10% of individuals with preclinical AD have coexisting LB pathology.
Topics: Humans; alpha-Synuclein; Lewy Bodies; tau Proteins; Cross-Sectional Studies; Alzheimer Disease; Lewy Body Disease; Amyloid beta-Peptides; Cognition; Cognitive Dysfunction; Biomarkers; Positron-Emission Tomography
PubMed: 37464059
DOI: 10.1038/s41591-023-02450-0 -
Journal of Cellular Physiology Oct 2020Parkinson's disease (PD) is one of the most common movement disorders with loss of dopaminergic neurons and the presence of Lewy bodies in certain brain areas. However,...
Parkinson's disease (PD) is one of the most common movement disorders with loss of dopaminergic neurons and the presence of Lewy bodies in certain brain areas. However, it is not clear how Lewy body (inclusion with protein aggregation) formation occurs. Mutations in leucine-rich repeat kinase 2 (LRRK2) can cause a genetic form of PD and contribute to sporadic PD with the typical Lewy body pathology. Here, we used our recently identified LRRK2 GTP-binding inhibitors as pharmacological probes to study the LRRK2-linked ubiquitination and protein aggregation. Pharmacological inhibition of GTP-binding by GTP-binding inhibitors (68 and Fx2149) increased LRRK2-linked ubiquitination predominantly via K27 linkage. Compound 68- or Fx2149 increased G2019S-LRRK2-linked ubiquitinated aggregates, which occurred through the atypical linkage types K27 and K63. Coexpression of K27R and K63R, which prevented ubiquitination via K27 and K63 linkages, reversed the effects of 68 and Fx2149. Moreover, 68 and Fx2149 also promoted G2019S-LRRK2-linked aggresome (Lewy body-like inclusion) formation via K27 and K63 linkages. These findings demonstrate that LRRK2 GTP-binding activity is critical in LRRK2-linked ubiquitination and aggregation formation. These studies provide novel insight into the LRRK2-linked Lewy body-like inclusion formation underlying PD pathogenesis.
Topics: Animals; Brain; Guanosine Triphosphate; HEK293 Cells; Humans; Inclusion Bodies; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Bodies; Mice; Mice, Inbred C57BL; Mutant Proteins; Mutation; Parkinson Disease; Protein Aggregation, Pathological; Protein Binding; Recombinant Proteins; Ubiquitination
PubMed: 32180220
DOI: 10.1002/jcp.29632 -
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 -
Brain Research Jan 2019This review provides an update about cardiac sympathetic denervation in Lewy body diseases. The family of Lewy body diseases includes Parkinson's disease (PD), pure... (Review)
Review
This review provides an update about cardiac sympathetic denervation in Lewy body diseases. The family of Lewy body diseases includes Parkinson's disease (PD), pure autonomic failure (PAF), and dementia with Lewy bodies (DLB). All three feature intra-neuronal cytoplasmic deposits of the protein, alpha-synuclein. Multiple system atrophy (MSA), the parkinsonian form of which can be difficult to distinguish from PD with orthostatic hypotension, involves glial cytoplasmic inclusions that contain alpha-synuclein. By now there is compelling neuroimaging, neuropathologic, and neurochemical evidence for cardiac sympathetic denervation in Lewy body diseases. In addition to denervation, there is decreased storage of catecholamines in the residual terminals. The degeneration develops in a centripetal, retrograde, "dying back" sequence. Across synucleinopathies the putamen and cardiac catecholaminergic lesions seem to occur independently of each other, whereas non-motor aspects of PD (e.g., anosmia, dementia, REM behavior disorder, OH) are associated with each other and with cardiac sympathetic denervation. Cardiac sympathetic denervation can be caused by synucleinopathy in inherited PD. According to the catecholaldehyde hypothesis, 3,4-dihydroxyphenylacetaldehyde (DOPAL), an intermediary metabolite of dopamine, causes or contributes to the death of catecholamine neurons, especially by interacting with proteins such as alpha-synuclein. DOPAL oxidizes spontaneously to DOPAL-quinone, which probably converts alpha-synuclein to its toxic oligomeric form. Decreasing DOPAL production and oxidation might slow the neurodegenerative process. Tracking cardiac sympathetic innervation over time could be the basis for a proof of principle experimental therapeutics trial targeting DOPAL.
Topics: 3,4-Dihydroxyphenylacetic Acid; Catecholamines; Dopamine; Heart; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Myocardium; Neuroimaging; Neurons; Parkinson Disease; Sympathetic Nervous System; alpha-Synuclein
PubMed: 29030055
DOI: 10.1016/j.brainres.2017.09.033 -
Journal of Neural Transmission (Vienna,... May 2023Since the description of some peculiar symptoms by James Parkinson in 1817, attempts have been made to define its cause or at least to enlighten the pathology of... (Review)
Review
Since the description of some peculiar symptoms by James Parkinson in 1817, attempts have been made to define its cause or at least to enlighten the pathology of "Parkinson's disease (PD)." The vast majority of PD subtypes and most cases of sporadic PD share Lewy bodies (LBs) as a characteristic pathological hallmark. However, the processes underlying LBs generation and its causal triggers are still unknown. ɑ-Synuclein (ɑ-syn, encoded by the SNCA gene) is a major component of LBs, and SNCA missense mutations or duplications/triplications are causal for rare hereditary forms of PD. Thus, it is imperative to study ɑ-syn protein and its pathology, including oligomerization, fibril formation, aggregation, and spreading mechanisms. Furthermore, there are synergistic effects in the underlying pathogenic mechanisms of PD, and multiple factors-contributing with different ratios-appear to be causal pathological triggers and progression factors. For example, oxidative stress, reduced antioxidative capacity, mitochondrial dysfunction, and proteasomal disturbances have each been suggested to be causal for ɑ-syn fibril formation and aggregation and to contribute to neuroinflammation and neural cell death. Aging is also a major risk factor for PD. Iron, as well as neuromelanin (NM), show age-dependent increases, and iron is significantly increased in the Parkinsonian substantia nigra (SN). Iron-induced pathological mechanisms include changes of the molecular structure of ɑ-syn. However, more recent PD research demonstrates that (i) LBs are detected not only in dopaminergic neurons and glia but in various neurotransmitter systems, (ii) sympathetic nerve fibres degenerate first, and (iii) at least in "brain-first" cases dopaminergic deficiency is evident before pathology induced by iron and NM. These recent findings support that the ɑ-syn/LBs pathology as well as iron- and NM-induced pathology in "brain-first" cases are important facts of PD pathology and via their interaction potentiate the disease process in the SN. As such, multifactorial toxic processes posted on a personal genetic risk are assumed to be causal for the neurodegenerative processes underlying PD. Differences in ratios of multiple factors and their spatiotemporal development, and the fact that common triggers of PD are hard to identify, imply the existence of several phenotypical subtypes, which is supported by arguments from both the "bottom-up/dual-hit" and "brain-first" models. Therapeutic strategies are necessary to avoid single initiation triggers leading to PD.
Topics: Humans; Parkinson Disease; Lewy Bodies; Iron; alpha-Synuclein; Inflammation
PubMed: 37062012
DOI: 10.1007/s00702-023-02630-9 -
Movement Disorders : Official Journal... May 2021Parkinson's disease (PD) is a progressive neurodegenerative disease where dopaminergic neurons in the substantia nigra are lost, resulting in a decrease in striatal... (Review)
Review
Parkinson'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.
Topics: Cholesterol; Glucosylceramidase; Humans; Lewy Bodies; Neurodegenerative Diseases; Parkinson Disease; alpha-Synuclein
PubMed: 33219714
DOI: 10.1002/mds.28396 -
Neurobiology of Disease Aug 2021Lewy bodies (LBs), one of the neuropathological defining hallmarks of Parkinson's disease (PD), are composed of a complex mixture of alpha-synuclein (aSyn) filaments and... (Review)
Review
Lewy bodies (LBs), one of the neuropathological defining hallmarks of Parkinson's disease (PD), are composed of a complex mixture of alpha-synuclein (aSyn) filaments and hundreds of proteins, lipids, and membranous organelles. However, these proteins' role in aSyn aggregation and the biogenesis of LBs remains poorly understood. Previous studies have focused on investigating the role of these proteins as modifiers of aSyn aggregation, inclusion formation, and toxicity; very often, one protein at a time. In a recent study, Ham et al. suggest that one of these proteins, aminoacyl tRNA synthase complex-interacting multifunctional protein 2 (AIMP2), plays a primary role in the initiation of aSyn aggregation and is essential for aSyn inclusion formation and toxicity in cells and several models of synucleinopathies (Ham et al., 2020). Based on in vitro aggregation studies, they proposed a model in which AIMP2 self-associates to form amyloid-like aggregates that interact with monomeric aSyn and catalyze/seed the formation of aSyn fibrils and, eventually, LB-like inclusions. Herein, we present a critical analysis of their results and conclusions, review previous studies on AIMP2 aggregation, and reexamine the role of AIMP2 in regulating aSyn inclusion formation and clearance and aSyn-induced neurodegeneration in Parkinson's disease. We conclude by presenting lesson learned and recommendations on experimental factors and approaches that should be considered in future studies aimed at investigating the potential of targeting LBs-associated proteins, including AIMP2, for developing therapies to treat PD and other synucleinopathies.
Topics: Animals; Humans; Lewy Bodies; Nuclear Proteins; Protein Aggregation, Pathological; Substantia Nigra; alpha-Synuclein
PubMed: 34102275
DOI: 10.1016/j.nbd.2021.105417 -
Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders.Acta Neuropathologica Apr 2021Accumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases,... (Review)
Review
Accumulation 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.
Topics: Hemochromatosis; Humans; Lewy Bodies; Lipid Metabolism; Lysosomal Storage Diseases; Lysosomes; Mitochondria; Mitochondrial Diseases; alpha-Synuclein
PubMed: 33515275
DOI: 10.1007/s00401-021-02266-7