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BACKGROUND: We recently identified three distinct Parkinson's disease subtypes: "motor only" (predominant motor deficits with intact cognition and psychiatric function); "psychiatric & motor" (prominent psychiatric symptoms and moderate motor deficits); "cognitive & motor" (cognitive and motor deficits). OBJECTIVE: We used an independent cohort to replicate and assess reliability of these Parkinson's disease subtypes. METHODS: We tested our original subtype classification with an independent cohort (N = 100) of Parkinson's disease participants without dementia and the same comprehensive evaluations assessing motor, cognitive, and psychiatric function. Next, we combined the original (N = 162) and replication (N = 100) datasets to test the classification model with the full combined dataset (N = 262). We also generated 10 random split-half samples of the combined dataset to establish the reliability of the subtype classifications. Latent class analyses were applied to the replication, combined, and split-half samples to determine subtype classification. RESULTS: First, LCA supported the three-class solution - Motor Only, Psychiatric & Motor, and Cognitive & Motor- in the replication sample. Next, using the larger, combined sample, LCA again supported the three subtype groups, with the emergence of a potential fourth group defined by more severe motor deficits. Finally, split-half analyses showed that the three-class model also had the best fit in 13/20 (65%) split-half samples; two-class and four-class solutions provided the best model fit in five (25%) and two (10%) split-half replications, respectively. CONCLUSIONS: These results support the reproducibility and reliability of the Parkinson's disease behavioral subtypes of motor only, psychiatric & motor, and cognitive & motor groups.
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Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/clasificación , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/diagnóstico , Femenino , Masculino , Reproducibilidad de los Resultados , Anciano , Persona de Mediana Edad , Estudios de Cohortes , Trastornos Mentales/clasificación , Trastornos Mentales/diagnóstico , Trastornos Mentales/etiología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/clasificación , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/diagnósticoRESUMEN
TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous system of some neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy (IBM). TDP-43 aggregates from ALS and FTD brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in IBM patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with IBM, IMNM and ALS we found that TDP-43 seeding capacity was specific to IBM. Surprisingly, TDP-43 seeding capacity anti-correlated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.
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Lysosomal membrane permeabilization caused either via phagocytosis of particulates or the uptake of protein aggregates can trigger the activation of NLRP3 inflammasome- an intense inflammatory response that drives the release of the pro-inflammatory cytokine IL-1ß by regulating the activity of CASPASE 1. The maintenance of lysosomal homeostasis and lysosomal membrane integrity is facilitated by the AAA+ ATPase, VCP/p97 (VCP). However, the relationship between VCP and NLRP3 inflammasome activity remains unexplored. Here, we demonstrate that the VCP inhibitors, DBeQ and ML240 elicit the activation of NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs) when used as activation stimuli. Moreover, genetic inhibition of VCP or VCP chemical inhibition enhances lysosomal membrane damage and augments LLoME-associated NLRP3 inflammasome activation in BMDMs. Similarly, VCP inactivation also augments NLRP3 inflammasome activation mediated by aggregated alpha-synuclein fibrils and lysosomal damage. These data suggest that VCP is a participant in the complex regulation of NLRP3 inflammasome activation.
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The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and approaches for studying disease mechanisms, imaging agents and therapeutics targeting Asyn.
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Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Humanos , alfa-Sinucleína/química , Microscopía por Crioelectrón , Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/patología , Enfermedad de Parkinson/patologíaRESUMEN
Fibrils of the protein α-synuclein (Asyn) are implicated in the pathogenesis of Parkinson Disease, Lewy Body Dementia, and Multiple System Atrophy. Numerous forms of Asyn fibrils have been studied by solid-state NMR and resonance assignments have been reported. Here, we report a new set of 13C, 15N assignments that are unique to fibrils obtained by amplification from postmortem brain tissue of a patient diagnosed with Lewy Body Dementia.
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Enfermedad por Cuerpos de Lewy , Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Humanos , alfa-Sinucleína/química , Enfermedad por Cuerpos de Lewy/patología , Resonancia Magnética Nuclear Biomolecular , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Atrofia de Múltiples Sistemas/metabolismo , Atrofia de Múltiples Sistemas/patologíaRESUMEN
Abnormal α-synuclein (α-syn) aggregation characterizes α-synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy (MSA). However, no suitable positron emission tomography (PET) radiotracer for imaging α-syn in PD and MSA exists currently. Our structure-activity relationship studies identified 4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide (4i) as a PET radiotracer candidate for imaging α-syn. In vitro assays revealed high binding of 4i to recombinant α-syn fibrils (inhibition constant (Ki) = 6.1 nM) and low affinity for amyloid beta (Aß) fibrils in Alzheimer's disease (AD) homogenates. However, [3H]4i also exhibited high specific binding to AD, progressive supranuclear palsy, and corticobasal degeneration tissues as well as PD and MSA tissues, suggesting notable affinity to tau. Nevertheless, the specific binding to pathologic α-syn aggregates in MSA post-mortem brain tissues was significantly higher than in PD tissues. This finding demonstrated the potential use of [11C]4i as a PET tracer for imaging α-syn in MSA patients. Nonhuman primate PET studies confirmed good brain uptake and rapid washout for [11C]4i.
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Enfermedad de Alzheimer , Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Animales , alfa-Sinucleína , Atrofia de Múltiples Sistemas/diagnóstico por imagen , Péptidos beta-Amiloides , Tomografía de Emisión de Positrones , Encéfalo/diagnóstico por imagenRESUMEN
Fibrils of the protein α-synuclein (Asyn) are implicated in the pathogenesis of Parkinson Disease, Lewy Body Dementia, and Multiple System Atrophy. Numerous forms of Asyn fibrils have been studied by solid-state NMR and resonance assignments have been reported. Here, we report a new set of 13C, 15N assignments that are unique to fibrils obtained by amplification from postmortem brain tissue of a patient diagnosed with Lewy Body Dementia.
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The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. We developed and validated a novel method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and used solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise two protofilaments with pseudo-21 helical screw symmetry, very low twist and an interface formed by antiparallel beta strands of residues 85-93. The fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural landscape of LBD Asyn fibrils and inform further studies of disease mechanisms, imaging agents and therapeutics targeting Asyn.
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Parkinson's disease (PD) is a neurodegenerative disorder characterized by chronic neuroinflammation, loss of dopaminergic neurons in the substantia nigra, and in several cases accumulation of alpha-synuclein fibril (α-syn) containing Lewy-bodies (LBs). Peripheral inflammation may play a causal role in inducing and perpetuating neuroinflammation in PD and accumulation of fibrillar α-syn has been reported at several peripheral sites including the gut and liver. Peripheral fibrillar α-syn may induce activation of monocytes via recognition by toll-like receptors (TLRs) and stimulation of downstream NF-κB signaling; however, the specific mechanism by which this occurs is not defined. In this study we utilized the THP-1 monocytic cell line to model the peripheral transcriptional response to preformed fibrillar (PFF) α-syn. Compared to monomeric α-syn, PFF α-syn displays overt inflammatory gene upregulation and pathway activation including broad pan-TLR signaling pathway activation and increases in TNF and IL1B gene expression. Notably, the non-canonical NF-κB signaling pathway gene and PD genome wide association study (GWAS) candidate NFKB2 was upregulated. Additionally, non-canonical NF-κB activation-associated RANK and CD40 pathways were also upregulated. Transcriptional-phenotype analysis suggests PFFs induce transcriptional programs associated with differentiation of monocytes towards macrophages and osteoclasts via non-canonical NF-κB signaling as a potential mechanism in which myeloid/monocyte cells may contribute to peripheral inflammation and pathogenesis in PD.
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Enfermedad de Parkinson , alfa-Sinucleína , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , alfa-Sinucleína/farmacología , FN-kappa B/metabolismo , Enfermedades Neuroinflamatorias , Estudio de Asociación del Genoma Completo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Inflamación , Transducción de SeñalRESUMEN
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.
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Enfermedad de Alzheimer , Enfermedad por Cuerpos de Lewy , Neocórtex , Enfermedad de Parkinson , Humanos , Cuerpos de Lewy/patología , Enfermedad de Parkinson/complicaciones , Enfermedad por Cuerpos de Lewy/patología , Neocórtex/patología , Enfermedad de Alzheimer/patologíaRESUMEN
BACKGROUND AND OBJECTIVES: People with Parkinson disease (PD) commonly experience cognitive decline, which may relate to increased α-synuclein, tau, and ß-amyloid accumulation. This study examines whether the different proteins predict longitudinal cognitive decline in PD. METHODS: All participants (PD n = 152, controls n = 52) were part of a longitudinal study and completed a lumbar puncture for CSF protein analysis (α-synuclein, total tau [tau], and ß-amyloid42 [ß-amyloid]), a ß-amyloid PET scan, and/or provided a blood sample for APOE genotype (ε4+, ε4-), which is a risk factor for ß-amyloid accumulation. Participants also had comprehensive, longitudinal clinical assessments of overall cognitive function and dementia status, as well as cognitive testing of attention, language, memory, and visuospatial and executive function. We used hierarchical linear growth models to examine whether the different protein metrics predict cognitive change and multivariate Cox proportional hazard models to predict time to dementia conversion. Akaike information criterion was used to compare models for best fit. RESULTS: Baseline measures of CSF ß-amyloid predicted decline for memory (p = 0.04) and overall cognitive function (p = 0.01). APOE genotypes showed a significant group (ε4+, ε4-) effect such that ε4+ individuals declined faster than ε4- individuals in visuospatial function (p = 0.03). Baseline ß-amyloid PET significantly predicted decline in all cognitive measures (all p ≤ 0.004). Neither baseline CSF α-synuclein nor tau predicted cognitive decline. All 3 ß-amyloid--related metrics (CSF, PET, APOE) also predicted time to dementia. Models with ß-amyloid PET as a predictor fit the data the best. DISCUSSION: Presence or risk of ß-amyloid accumulation consistently predicted cognitive decline and time to dementia in PD. This suggests that ß-amyloid has high potential as a prognostic indicator and biomarker for cognitive changes in PD.
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Disfunción Cognitiva , Demencia , Enfermedad de Parkinson , Péptidos beta-Amiloides/metabolismo , Apolipoproteínas E , Biomarcadores , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Demencia/complicaciones , Humanos , Estudios Longitudinales , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/genética , Tomografía de Emisión de Positrones , alfa-Sinucleína , Proteínas tauRESUMEN
BACKGROUND: Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. METHODS: We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. RESULTS: One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. CONCLUSION: Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP's surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP.
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Proteínas de Unión al ADN , Neuronas , Animales , Proteínas de Unión al ADN/metabolismo , Humanos , Ratones , Mutación , Neuronas/metabolismo , Proteína que Contiene Valosina/genética , Proteína que Contiene Valosina/metabolismoRESUMEN
OBJECTIVE: Parkinson disease (PD) is defined by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies and Lewy neurites. It affects multiple cortical and subcortical neuronal populations. The majority of people with PD develop dementia, which is associated with Lewy bodies in neocortex and referred to as Lewy body dementia (LBD). Other neuropathologic changes, including amyloid ß (Aß) and tau accumulation, occur in some LBD cases. We sought to quantify α-syn, Aß, and tau accumulation in neocortical, limbic, and basal ganglia regions. METHODS: We isolated insoluble protein from fresh frozen postmortem brain tissue samples for eight brains regions from 15 LBD, seven Alzheimer disease (AD), and six control cases. We measured insoluble α-syn, Aß, and tau with recently developed sandwich ELISAs. RESULTS: We detected a wide range of insoluble α-syn accumulation in LBD cases. The majority had substantial α-syn accumulation in most regions, and dementia severity correlated with neocortical α-syn. However, three cases had low neocortical levels that were indistinguishable from controls. Eight LBD cases had substantial Aß accumulation, although the mean Aß level in LBD was lower than in AD. The presence of Aß was associated with greater α-syn accumulation. Tau accumulation accompanied Aß in only one LBD case. INTERPRETATION: LBD is associated with insoluble α-syn accumulation in neocortical regions, but the relatively low neocortical levels in some cases suggest that other changes contribute to impaired function, such as loss of neocortical innervation from subcortical regions. The correlation between Aß and α-syn accumulation suggests a pathophysiologic relationship between these two processes.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/análisis , Encéfalo/metabolismo , Enfermedad por Cuerpos de Lewy/metabolismo , alfa-Sinucleína/análisis , Proteínas tau/análisis , Anciano , Anciano de 80 o más Años , Autopsia , Humanos , Neocórtex/metabolismoRESUMEN
BACKGROUND: The clinical diagnosis of Parkinson's disease (PD) requires the presence of parkinsonism and supportive criteria that include a clear and dramatic beneficial response to dopaminergic therapy. Our aim was to test the diagnostic criterion of dopaminergic response by evaluating its association with pathologically confirmed diagnoses in a large population of parkinsonian patients. METHODS: We reviewed clinical data maintained in an electronic medical record from all patients with autopsy data who had been seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2018. All patients with parkinsonism who underwent postmortem neuropathologic examination were included in this analysis. RESULTS: There were 257 unique parkinsonian patients with autopsy-based diagnoses who had received dopaminergic therapy. Marked or moderate response to dopaminergic therapy occurred in 91.2% (166/182) of those with autopsy-confirmed PD, 52.0% (13/25) of those with autopsy-confirmed multiple systems atrophy, 44.4% (8/18) of those with autopsy-confirmed progressive supranuclear palsy, and 1 (1/8) with autopsy-confirmed corticobasal degeneration. Other diagnoses were responsible for the remaining 24 individuals, 9 of whom had a moderate response to dopaminergic therapy. CONCLUSION: A substantial response to dopaminergic therapy is frequent but not universal in PD. An absent response does not exclude PD. In other neurodegenerative disorders associated with parkinsonism, a prominent response may also be evident, but this occurs less frequently than in PD. © 2020 International Parkinson and Movement Disorder Society.
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Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Trastornos Parkinsonianos , Parálisis Supranuclear Progresiva , Humanos , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta1-42, total tau, and phosphorylated tau181 as quantitative traits in genetic studies have provided novel insights into Alzheimer's disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson's disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson's disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta1-42 levels (effect = - 0.5, p = 9.2 × 10-19). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau181 levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson's disease risk meta-analysis were associated with Parkinson's disease status (p = 0.035) and the genomic architecture of CSF amyloid beta1-42 (R2 = 2.29%; p = 2.5 × 10-11). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta1-42 levels (p = 7.3 × 10-04). Two-sample Mendelian Randomization revealed that CSF amyloid beta1-42 plays a role in Parkinson's disease (p = 1.4 × 10-05) and age at onset (p = 7.6 × 10-06), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta1-42 (p = 3.8 × 10-06), higher mean cortical binding potentials (p = 5.8 × 10-08), and higher Braak amyloid beta score (p = 4.4 × 10-04). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson's disease, CSF amyloid beta1-42, and APOE.
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Péptidos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Encéfalo/metabolismo , Enfermedad de Parkinson/genética , Fragmentos de Péptidos/metabolismo , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteína E4/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Fragmentos de Péptidos/líquido cefalorraquídeo , Fosforilación , alfa-Sinucleína/líquido cefalorraquídeo , alfa-Sinucleína/metabolismo , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/metabolismoRESUMEN
Tau hyperphosphorylation is an early step in tau-mediated neurodegeneration and is associated with intracellular aggregation of tau as neurofibrillary tangles, neuronal and synaptic loss, and eventual cognitive dysfunction in Alzheimer disease. Sleep loss increases the cerebrospinal fluid concentration of amyloid-ß and tau. Using mass spectrometry, we measured tau and phosphorylated tau concentrations in serial samples of cerebrospinal fluid collected from participants who were sleep-deprived, treated with sodium oxybate, or allowed to sleep normally. We found that sleep loss affected phosphorylated tau differently depending on the modified site. These findings suggest a mechanism for sleep loss to increase risk of Alzheimer disease. ANN NEUROL 2020;87:700-709.
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Privación de Sueño/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/metabolismo , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , FosforilaciónRESUMEN
Apolipoprotein E (APOE) ε4 genotype is associated with increased risk of dementia in Parkinson's disease (PD), but the mechanism is not clear, because patients often have a mixture of α-synuclein (αSyn), amyloid-ß (Aß), and tau pathologies. APOE ε4 exacerbates brain Aß pathology, as well as tau pathology, but it is not clear whether APOE genotype independently regulates αSyn pathology. In this study, we generated A53T αSyn transgenic mice (A53T) on Apoe knockout (A53T/EKO) or human APOE knockin backgrounds (A53T/E2, E3, and E4). At 12 months of age, A53T/E4 mice accumulated higher amounts of brainstem detergent-insoluble phosphorylated αSyn compared to A53T/EKO and A53T/E3; detergent-insoluble αSyn in A53T/E2 mice was undetectable. By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated αSyn and reactive gliosis compared to A53T/E2 mice. A53T/E2 mice exhibited increased survival and improved motor performance compared to other APOE genotypes. In a complementary model of αSyn spreading, striatal injection of αSyn preformed fibrils induced greater accumulation of αSyn pathology in the substantia nigra of A53T/E4 mice compared to A53T/E2 and A53T/EKO mice. In two separate cohorts of human patients with PD, APOE ε4/ε4 individuals showed the fastest rate of cognitive decline over time. Our results demonstrate that APOE genotype directly regulates αSyn pathology independent of its established effects on Aß and tau, corroborate the finding that APOE ε4 exacerbates pathology, and suggest that APOE ε2 may protect against αSyn aggregation and neurodegeneration in synucleinopathies.
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Sinucleinopatías , Animales , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Progresión de la Enfermedad , Genotipo , Humanos , RatonesRESUMEN
OBJECTIVE: To evaluate resting-state functional connectivity as a potential prognostic biomarker of Parkinson disease (PD) progression. The study examined longitudinal changes in cortical resting-state functional connectivity networks in participants with PD compared to controls as well as in relation to baseline protein measures and longitudinal clinical progression. METHODS: Individuals with PD without dementia (n = 64) and control participants (n = 27) completed longitudinal resting-state MRI scans and clinical assessments including full neuropsychological testing after overnight withdrawal of PD medications ("off"). A total of 55 participants with PD and 20 control participants also completed baseline ß-amyloid PET scans and lumbar punctures for CSF protein levels of α-synuclein, ß-amyloid, and tau. Longitudinal analyses were conducted with multilevel growth curve modeling, a type of mixed-effects model. RESULTS: Functional connectivity within the sensorimotor network and the interaction between the dorsal attention network with the frontoparietal control network decreased significantly over time in participants with PD compared to controls. Baseline CSF α-synuclein protein levels predicted decline in the sensorimotor network. The longitudinal decline in the dorsal attention-frontoparietal internetwork strength correlated with the decline in cognitive function. CONCLUSIONS: These results indicate that α-synuclein levels may influence longitudinal declines in motor-related functional connectivity networks. Further, the interaction between cortical association networks declines over time in PD prior to dementia onset and may serve as a prognostic marker for the development of dementia.
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Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/fisiopatología , Deficiencias en la Proteostasis/diagnóstico por imagen , Deficiencias en la Proteostasis/fisiopatología , Anciano , Biomarcadores/líquido cefalorraquídeo , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiopatología , Tomografía de Emisión de Positrones , DescansoRESUMEN
Aggregates of the RNA-binding protein TDP-43 (TAR DNA-binding protein) are a hallmark of the overlapping neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The process of TDP-43 aggregation remains poorly understood, and whether it includes formation of intermediate complexes is unknown. Here, we analyzed aggregates derived from purified TDP-43 under semidenaturing conditions, identifying distinct oligomeric complexes at the initial time points before the formation of large aggregates. We found that this early oligomerization stage is primarily driven by TDP-43's RNA-binding region. Specific binding to GU-rich RNA strongly inhibited both TDP-43 oligomerization and aggregation, suggesting that RNA interactions are critical for maintaining TDP-43 solubility. Moreover, we analyzed TDP-43 liquid-liquid phase separation and detected similar detergent-resistant oligomers upon maturation of liquid droplets into solid-like fibrils. These results strongly suggest that the oligomers form during the early steps of TDP-43 misfolding. Importantly, the ALS-linked TDP-43 mutations A315T and M337V significantly accelerate aggregation, rapidly decreasing the monomeric population and shortening the oligomeric phase. We also show that aggregates generated from purified TDP-43 seed intracellular aggregation detected by established TDP-43 pathology markers. Remarkably, cytoplasmic aggregate seeding was detected earlier for the A315T and M337V variants and was 50% more widespread than for WT TDP-43 aggregates. We provide evidence for an initial step of TDP-43 self-assembly into intermediate oligomeric complexes, whereby these complexes may provide a scaffold for aggregation. This process is altered by ALS-linked mutations, underscoring the role of perturbations in TDP-43 homeostasis in protein aggregation and ALS-FTD pathogenesis.
Asunto(s)
Biopolímeros/metabolismo , Proteínas de Unión al ADN/metabolismo , Esclerosis Amiotrófica Lateral/metabolismo , Biomarcadores/metabolismo , Proteínas de Unión al ADN/genética , Disulfuros/metabolismo , Células HEK293 , Humanos , Peso Molecular , Mutación , Transición de Fase , Pliegue de Proteína , Proteínas de Unión al ARN/metabolismo , Proteínas Recombinantes/metabolismoRESUMEN
Parkinson's disease (PD) and multiple system atrophy (MSA) are distinct clinical syndromes characterized by the pathological accumulation of α-synuclein (α-syn) protein fibrils in neurons and glial cells. These disorders and other neurodegenerative diseases may progress via prion-like mechanisms. The prion model of propagation predicts the existence of "strains" that link pathological aggregate structure and neuropathology. Prion strains are aggregated conformers that stably propagate in vivo and cause disease with defined incubation times and patterns of neuropathology. Indeed, tau prions have been well defined, and research suggests that both α-syn and ß-amyloid may also form strains. However, there is a lack of studies characterizing PD- versus MSA-derived α-syn strains or demonstrating stable propagation of these unique conformers between cells or animals. To fill this gap, we used an assay based on FRET that exploits a HEK293T "biosensor" cell line stably expressing α-syn (A53T)-CFP/YFP fusion proteins to detect α-syn seeds in brain extracts from PD and MSA patients. Both soluble and insoluble fractions of MSA extracts had robust seeding activity, whereas only the insoluble fractions of PD extracts displayed seeding activity. The morphology of MSA-seeded inclusions differed from PD-seeded inclusions. These differences persisted upon propagation of aggregation to second-generation biosensor cells. We conclude that PD and MSA feature α-syn conformers with very distinct biochemical properties that can be transmitted to α-syn monomers in a cell system. These findings are consistent with the idea that distinct α-syn strains underlie PD and MSA and offer possible directions for synucleinopathy diagnosis.