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1.
Cell ; 185(12): 2035-2056.e33, 2022 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-35688132

RESUMO

Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.


Assuntos
Doença de Parkinson , alfa-Sinucleína , Humanos , Doença de Parkinson/metabolismo , Corpos de Processamento , Estabilidade de RNA , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
2.
Mol Cell ; 73(5): 1001-1014.e8, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30527540

RESUMO

In Parkinson's disease (PD), α-synuclein (αS) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in αS or lipid/fatty acid homeostasis affect each other. Lipidomic profiling of human αS-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides. These findings were recapitulated in rodent and human neuronal models of αS dyshomeostasis (overexpression; patient-derived triplication or E46K mutation; E46K mice). Preventing lipid droplet formation or augmenting OA increased αS yeast toxicity; suppressing the OA-generating enzyme stearoyl-CoA-desaturase (SCD) was protective. Genetic or pharmacological SCD inhibition ameliorated toxicity in αS-overexpressing rat neurons. In a C. elegans model, SCD knockout prevented αS-induced dopaminergic degeneration. Conversely, we observed detrimental effects of OA on αS homeostasis: in human neural cells, excess OA caused αS inclusion formation, which was reversed by SCD inhibition. Thus, monounsaturated fatty acid metabolism is pivotal for αS-induced neurotoxicity, and inhibiting SCD represents a novel PD therapeutic approach.


Assuntos
Antiparkinsonianos/farmacologia , Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolômica/métodos , Neurônios/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Estearoil-CoA Dessaturase/antagonistas & inibidores , alfa-Sinucleína/toxicidade , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/genética , Linhagem Celular , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Diglicerídeos/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/enzimologia , Neurônios Dopaminérgicos/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/enzimologia , Células-Tronco Pluripotentes Induzidas/patologia , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/enzimologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Terapia de Alvo Molecular , Degeneração Neural , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/enzimologia , Células-Tronco Neurais/patologia , Neurônios/enzimologia , Neurônios/patologia , Ácido Oleico/metabolismo , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Ratos Sprague-Dawley , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética , Estearoil-CoA Dessaturase/metabolismo , Triglicerídeos/metabolismo , alfa-Sinucleína/genética
3.
Proc Natl Acad Sci U S A ; 121(1): e2312306120, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38147546

RESUMO

The neuron-to-neuron propagation of misfolded α-synuclein (αSyn) aggregates is thought to be key to the pathogenesis of synucleinopathies. Recent studies have shown that extracellular αSyn aggregates taken up by the endosomal-lysosomal system can rupture the lysosomal vesicular membrane; however, it remains unclear whether lysosomal rupture leads to the transmission of αSyn aggregation. Here, we applied cell-based αSyn propagation models to show that ruptured lysosomes are the pathway through which exogenous αSyn aggregates transmit aggregation, and furthermore, this process was prevented by lysophagy, i.e., selective autophagy of damaged lysosomes. αSyn aggregates accumulated predominantly in lysosomes, causing their rupture, and seeded the aggregation of endogenous αSyn, initially around damaged lysosomes. Exogenous αSyn aggregates induced the accumulation of LC3 on lysosomes. This LC3 accumulation was not observed in cells in which a key regulator of autophagy, RB1CC1/FIP200, was knocked out and was confirmed as lysophagy by transmission electron microscopy. Importantly, RB1CC1/FIP200-deficient cells treated with αSyn aggregates had increased numbers of ruptured lysosomes and enhanced propagation of αSyn aggregation. Furthermore, various types of lysosomal damage induced using lysosomotropic reagents, depletion of lysosomal enzymes, or more toxic species of αSyn fibrils also exacerbated the propagation of αSyn aggregation, and impaired lysophagy and lysosomal membrane damage synergistically enhanced propagation. These results indicate that lysophagy prevents exogenous αSyn aggregates from escaping the endosomal-lysosomal system and transmitting aggregation to endogenous cytosolic αSyn via ruptured lysosomal vesicles. Our findings suggest that the progression and severity of synucleinopathies are associated with damage to lysosomal membranes and impaired lysophagy.


Assuntos
Doença de Parkinson , Sinucleinopatias , Humanos , alfa-Sinucleína/metabolismo , Macroautofagia , Sinucleinopatias/metabolismo , Doença de Parkinson/metabolismo , Lisossomos/metabolismo
4.
EMBO Rep ; 24(12): e57145, 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-37870370

RESUMO

α-Synuclein phosphorylation at serine-129 (pS129) is a widely used surrogate marker of pathology in Parkinson's disease and other synucleinopathies. However, we recently demonstrated that phosphorylation of S129 is also a physiological activator of synaptic transmission. In a feed-forward fashion, neuronal activity triggers reversible pS129. Here, we show that Parkinson's disease-linked missense mutations in SNCA impact activity-dependent pS129. Under basal conditions, cytosol-enriched A30P, H50Q, and G51D mutant forms of α-synuclein exhibit reduced pS129 levels in rat primary cortical neurons. A53T pS129 levels are similar to wild-type, and E46K pS129 levels are higher. A30P and E46K mutants show impaired reversibility of pS129 after stimulation. For the engineered profoundly membrane-associated α-synuclein mutant "3K" (E35K + E46K + E61K), de-phosphorylation was virtually absent after blocking stimulation, implying that reversible pS129 is severely compromised. Importantly, pS129 excess resulting from proteasome inhibition is also associated with reduced reversibility by neuronal inhibition, kinase inhibition, or phosphatase activation. Our findings suggest that perturbed pS129 dynamics are probably a shared characteristic of pathology-associated α-synuclein, with possible implications for synucleinopathy treatment and diagnosis.


Assuntos
Doença de Parkinson , Sinucleinopatias , Animais , Ratos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologia , Serina/metabolismo , Fosforilação
5.
Brain ; 147(1): 81-90, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-37526295

RESUMO

Parkinson's disease is clinically known for the loss of dopaminergic neurons in the substantia nigra pars compacta and accumulation of intraneuronal cytoplasmic inclusions rich in alpha-synuclein called 'Lewy bodies' and 'Lewy neurites'. Together with dementia with Lewy bodies and multiple system atrophy, Parkinson's disease is part of a group of disorders called synucleinopathies. Currently, diagnosis of synucleinopathies is based on the clinical assessment which often takes place in advanced disease stages. While the causal role of alpha-synuclein aggregates in these disorders is still debatable, measuring the levels, types or seeding properties of different alpha-synuclein species hold great promise as biomarkers. Recent studies indicate significant differences in peptide, protein and RNA levels in blood samples from patients with Parkinson's disease. Seed amplification assays using CSF, blood, skin biopsy, olfactory swab samples show great promise for detecting synucleinopathies and even for discriminating between different synucleinopathies. Interestingly, small extracellular vesicles, such as exosomes, display differences in their cargoes in Parkinson's disease patients versus controls. In this update, we focus on alpha-synuclein aggregation and possible sources of disease-related species released in extracellular vesicles, which promise to revolutionize the diagnosis and the monitoring of disease progression.


Assuntos
Exossomos , Doença de Parkinson , Sinucleinopatias , Humanos , alfa-Sinucleína/metabolismo , Sinucleinopatias/patologia , Doença de Parkinson/metabolismo , Exossomos/metabolismo , Biomarcadores
6.
Brain ; 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39252645

RESUMO

Visual hallucinations are a common non-motor feature of Parkinson's disease and have been associated with accelerated cognitive decline, increased mortality and early institutionalisation. Despite their prevalence and negative impact on patient outcomes, the repertoire of treatments aimed at addressing this troubling symptom is limited. Over the last two decades, significant contributions have been made in uncovering the pathological and functional mechanisms of visual hallucinations, bringing us closer to the development of a comprehensive neurobiological framework. Convergent evidence now suggests that degeneration within the central cholinergic system may play a significant role in the genesis and progression of visual hallucinations. Here, we outline how cholinergic dysfunction may serve as a potential unifying neurobiological substrate underlying the multifactorial and dynamic nature of visual hallucinations. Drawing upon previous theoretical models, we explore the impact that alterations in cholinergic neurotransmission has on the core cognitive processes pertinent to abnormal perceptual experiences. We conclude by highlighting that a deeper understanding of cholinergic neurobiology and individual pathophysiology may help to improve established and emerging treatment strategies for the management of visual hallucinations and psychotic symptoms in Parkinson's disease.

7.
J Neurochem ; 168(9): 2926-2934, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38943336

RESUMO

The synucleinopathies Parkinson disease (PD), multiple system atrophy (MSA), and the Lewy body form of pure autonomic failure (PAF) entail intra-cytoplasmic deposition of the protein alpha-synuclein and pathogenic catecholaminergic neurodegeneration. Cerebrospinal fluid (CSF) levels of catecholamines and their metabolites are thought to provide a "neurochemical window" on central catecholaminergic innervation and can identify specific intra-neuronal dysfunctions in synucleinopathies. We asked whether there are CSF concentration gradients for catechols such as 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, and if so whether the gradients influence neurochemical differences among synucleinopathies. In a retrospective cohort study, we reviewed data about concentrations of catechols in the first, sixth, and twelfth 1-mL aliquots from 33 PD, 28 MSA, and 15 PAF patients and 41 controls. There were concentration gradients for DOPAC, dopamine, norepinephrine, and 3,4-dihydroxyphenylglycol (the main neuronal metabolite of norepinephrine) and gradients in the opposite direction for 5-S-cysteinyldopa and 5-S-cysteinyldopamine. In all 3 aliquots, CSF DOPAC was low in PD and MSA compared with controls (p < 0.0001 each) and normal in PAF. Synucleinopathies differ in CSF catechols regardless of concentration gradients. Concentration gradients for 5-S-cysteinyl derivatives in opposite directions from the parent catechols may provide biomarkers of spontaneous oxidation in the CSF space.


Assuntos
Catecóis , Sinucleinopatias , Humanos , Idoso , Masculino , Feminino , Pessoa de Meia-Idade , Sinucleinopatias/líquido cefalorraquidiano , Sinucleinopatias/metabolismo , Catecóis/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/metabolismo , Estudos Retrospectivos , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Atrofia de Múltiplos Sistemas/metabolismo , Estudos de Coortes , Dopamina/líquido cefalorraquidiano , Dopamina/metabolismo , Insuficiência Autonômica Pura/líquido cefalorraquidiano
8.
Neurobiol Dis ; 201: 106646, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39181187

RESUMO

Parkinson's disease (PD), the second most common neurodegenerative disease worldwide, is marked by the presence of Lewy bodies and Lewy neurites, neuronal lesions containing large amounts of the synaptic protein alpha-synuclein (αS). While the underlying mechanisms of disease progression in PD remain unclear, increasing evidence supports the importance of interactions between αS and cellular membranes in PD pathology. Therefore, understanding the αS-membrane interplay in health and disease is crucial for the development of therapeutic strategies. In this review, we (1) discuss key scenarios of pathological αS-membrane interactions; (2) present in detail therapeutic strategies explicitly reported to modify αS-membrane interactions; and (3) introduce additional therapeutic strategies that may involve aspects of interfering with αS-membrane interaction. This way, we aim to provide a holistic perspective on this important aspect of disease-modifying strategies for PD and other α-synucleinopathies.


Assuntos
Membrana Celular , Doença de Parkinson , alfa-Sinucleína , alfa-Sinucleína/metabolismo , Humanos , Doença de Parkinson/metabolismo , Doença de Parkinson/tratamento farmacológico , Animais , Membrana Celular/metabolismo
9.
Neurobiol Dis ; 191: 106411, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38228253

RESUMO

Parkinson's disease (PD) pathology is characterized by alpha-synuclein (α-syn) aggregates, degeneration of dopamine neurons in the substantia nigra pars compacta (SNpc), and neuroinflammation. The presence of reactive glia correlates with deposition of pathological α-syn in early-stage PD. Thus, understanding the neuroinflammatory response of microglia and astrocytes to synucleinopathy may identify therapeutic targets. Here we characterized the neuroinflammatory gene expression profile of reactive microglia and astrocytes in the SNpc during early synucleinopathy in the rat α-syn pre-formed fibril (PFF) model. Rats received intrastriatal injection of α-syn PFFs and expression of immune genes was quantified with droplet digital PCR (ddPCR), after which fluorescent in situ hybridization (FISH) was used to localize gene expression to microglia or astrocytes in the SNpc. Genes previously associated with reactive microglia (Cd74, C1qa, Stat1, Axl, Casp1, Il18, Lyz2) and reactive astrocytes (C3, Gbp2, Serping1) were significantly upregulated in the SN of PFF injected rats. Localization of gene expression to SNpc microglia near α-syn aggregates identified a unique α-syn aggregate microglial gene expression profile characterized by upregulation of Cd74, Cxcl10, Rt-1a2, Grn, Csf1r, Tyrobp, C3, C1qa, Serping1 and Fcer1g. Importantly, significant microglial upregulation of Cd74 and C3 were only observed following injection of α-syn PFFs, not α-syn monomer, confirming specificity to α-syn aggregation. Serping1 expression also localized to astrocytes in the SNpc. Interestingly, C3 expression in the SNpc localized to microglia at 2- and 4-months post-PFF, but to astrocytes at 6-months post-PFF. We also observed expression of Rt1-a2 and Cxcl10 in SNpc dopamine neurons. Cumulatively our results identify a dynamic, yet reproducible gene expression profile of reactive microglia and astrocytes associated with early synucleinopathy in the rat SNpc.


Assuntos
Doença de Parkinson , Sinucleinopatias , Animais , Ratos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Proteína Inibidora do Complemento C1/genética , Proteína Inibidora do Complemento C1/metabolismo , Neurônios Dopaminérgicos/metabolismo , Hibridização in Situ Fluorescente , Neuroglia/metabolismo , Doenças Neuroinflamatórias , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , Sinucleinopatias/patologia , Transcriptoma
10.
Eur J Neurosci ; 59(1): 132-153, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38072889

RESUMO

The existent pre-clinical models of Parkinson's disease do not simultaneously recapitulate severe degeneration of dopamine neurons and the occurrence of alpha-synuclein (aSyn) aggregation in one study system. In this study, we injected aSyn pre-formed fibrils (PFF) and 6-hydroxydopamine (6-OHDA) unilaterally into the striatum of C57BL/6 wild-type male mice at an interval of 2 weeks to induce aggregation of aSyn protein and trigger the loss of dopamine neurons simultaneously in one model and studied the behavioural effects of the combination in these mice. 6-OHDA was tested at three different doses, and 2 µg of 6-OHDA combined with PFF-induced aSyn aggregation was found to produce the most optimal disease phenotype. At 14 weeks timepoint, mice injected with a combination of PFF and 6-OHDA sustained significant damage to the nigrostriatal pathway and exhibited aSyn-positive aggregation. Our data suggest that the neurons that formed large aSyn aggregates were particularly vulnerable to 6-OHDA-induced degeneration. We also demonstrate the manifestation of a relatively aggressive pathology in 2- to 4-month-old mice, as compared to younger 7- to 9-week-old ones. Furthermore, cerebral dopamine neurotrophic factor (CDNF) administered intrastriatally rescued dopamine neurons and motor behaviour of the animals to some extent from 6-OHDA toxicity. However, no such effect could be seen in the novel 6-OHDA + PFFs combination model. For the first time, we demonstrate the combined effect of PFF and 6-OHDA simultaneously in one model. We further discuss the scope for further optimizing this combination model to develop it as a promising pre-clinical platform for drug screening and development.


Assuntos
Doença de Parkinson , alfa-Sinucleína , Animais , Masculino , Camundongos , alfa-Sinucleína/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/farmacologia , Oxidopamina , Doença de Parkinson/metabolismo
11.
J Neuroinflammation ; 21(1): 108, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664840

RESUMO

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies), markers of neuroinflammation and the progressive loss of nigrostriatal dopamine (DA) neurons. These pathological features can be recapitulated in vivo using the α-syn preformed fibril (PFF) model of synucleinopathy. We have previously determined that microglia proximal to PFF-induced nigral α-syn inclusions increase in soma size, upregulate major-histocompatibility complex-II (MHC-II) expression, and increase expression of a suite of inflammation-associated transcripts. This microglial response is observed months prior to degeneration, suggesting that microglia reacting to α-syn inclusion may contribute to neurodegeneration and could represent a potential target for novel therapeutics. The goal of this study was to determine whether colony stimulating factor-1 receptor (CSF1R)-mediated microglial depletion impacts the magnitude of α-syn aggregation, nigrostriatal degeneration, or the response of microglial in the context of the α-syn PFF model. METHODS: Male Fischer 344 rats were injected intrastriatally with either α-syn PFFs or saline. Rats were continuously administered Pexidartinib (PLX3397B, 600 mg/kg), a CSF1R inhibitor, to deplete microglia for a period of either 2 or 6 months. RESULTS: CSF1R inhibition resulted in significant depletion (~ 43%) of ionized calcium-binding adapter molecule 1 immunoreactive (Iba-1ir) microglia within the SNpc. However, CSF1R inhibition did not impact the increase in microglial number, soma size, number of MHC-II immunoreactive microglia or microglial expression of Cd74, Cxcl10, Rt-1a2, Grn, Csf1r, Tyrobp, and Fcer1g associated with phosphorylated α-syn (pSyn) nigral inclusions. Further, accumulation of pSyn and degeneration of nigral neurons was not impacted by CSF1R inhibition. Paradoxically, long term CSF1R inhibition resulted in increased soma size of remaining Iba-1ir microglia in both control and PFF rats, as well as expression of MHC-II in extranigral regions. CONCLUSIONS: Collectively, our results suggest that CSF1R inhibition does not impact the microglial response to nigral pSyn inclusions and that CSF1R inhibition is not a viable disease-modifying strategy for PD.


Assuntos
Microglia , Ratos Endogâmicos F344 , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , alfa-Sinucleína , Animais , Microglia/metabolismo , Microglia/efeitos dos fármacos , alfa-Sinucleína/metabolismo , Ratos , Masculino , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Pirróis/farmacologia , Aminopiridinas/farmacologia , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Substância Negra/metabolismo , Substância Negra/patologia , Substância Negra/efeitos dos fármacos , Modelos Animais de Doenças
12.
Mov Disord ; 39(8): 1397-1402, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38561921

RESUMO

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is considered as a prodromal stage of synucleinopathies. Fecal short-chain fatty acid (SCFA) changes in iRBD and the relationships with synucleinopathies have never been investigated. OBJECTIVES: To investigate fecal SCFA changes among iRBD, multiple system atrophy (MSA), and Parkinson's disease (PD), and evaluate their relationships. METHODS: Fecal SCFAs and gut microbiota were measured in 29 iRBD, 42 MSA, 40 PD, and 35 normal controls (NC) using gas chromatography-mass spectrometry and 16S rRNA gene sequencing. RESULTS: Compared with NC, fecal SCFA levels (propionic, acetic, and butyric acid) were lower in iRBD, MSA, and PD. Combinations of these SCFAs could differentiate NC from iRBD (AUC 0.809), MSA (AUC 0.794), and PD (AUC 0.701). Decreased fecal SCFAs were associated with the common reducing SCFA-producing gut microbiota in iRBD, MSA, and PD. CONCLUSIONS: iRBD shares similar fecal SCFA alterations with MSA and PD, and the combination of these SCFAs might be a potential synucleinopathies-related biomarker. © 2024 International Parkinson and Movement Disorder Society.


Assuntos
Ácidos Graxos Voláteis , Fezes , Microbioma Gastrointestinal , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtorno do Comportamento do Sono REM , Humanos , Atrofia de Múltiplos Sistemas/metabolismo , Transtorno do Comportamento do Sono REM/metabolismo , Doença de Parkinson/metabolismo , Fezes/química , Fezes/microbiologia , Masculino , Feminino , Ácidos Graxos Voláteis/metabolismo , Ácidos Graxos Voláteis/análise , Idoso , Pessoa de Meia-Idade , Microbioma Gastrointestinal/fisiologia
13.
Mov Disord ; 39(10): 1752-1762, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39001636

RESUMO

BACKGROUND: Speech dysfunction represents one of the initial motor manifestations to develop in Parkinson's disease (PD) and is measurable through smartphone. OBJECTIVE: The aim was to develop a fully automated and noise-resistant smartphone-based system that can unobtrusively screen for prodromal parkinsonian speech disorder in subjects with isolated rapid eye movement sleep behavior disorder (iRBD) in a real-world scenario. METHODS: This cross-sectional study assessed regular, everyday voice call data from individuals with iRBD compared to early PD patients and healthy controls via a developed smartphone application. The participants also performed an active, regular reading of a short passage on their smartphone. Smartphone data were continuously collected for up to 3 months after the standard in-person assessments at the clinic. RESULTS: A total of 3525 calls that led to 5990 minutes of preprocessed speech were extracted from 72 participants, comprising 21 iRBD patients, 26 PD patients, and 25 controls. With a high area under the curve of 0.85 between iRBD patients and controls, the combination of passive and active smartphone data provided a comparable or even more sensitive evaluation than laboratory examination using a high-quality microphone. The most sensitive features to induce prodromal neurodegeneration in iRBD included imprecise vowel articulation during phone calls (P = 0.03) and monopitch in reading (P = 0.05). Eighteen minutes of speech corresponding to approximately nine calls was sufficient to obtain the best sensitivity for the screening. CONCLUSION: We consider the developed tool widely applicable to deep longitudinal digital phenotyping data with future applications in neuroprotective trials, deep brain stimulation optimization, neuropsychiatry, speech therapy, population screening, and beyond. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doença de Parkinson , Transtorno do Comportamento do Sono REM , Smartphone , Humanos , Transtorno do Comportamento do Sono REM/fisiopatologia , Transtorno do Comportamento do Sono REM/diagnóstico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Estudos Transversais , Doença de Parkinson/fisiopatologia , Doença de Parkinson/complicações , Biomarcadores , Voz/fisiologia , Transtornos Parkinsonianos/fisiopatologia , Sintomas Prodrômicos , Distúrbios da Fala/etiologia
14.
Cell Mol Neurobiol ; 44(1): 42, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38668880

RESUMO

Lewy Body Dementias (LBD), including Parkinson's disease dementia and Dementia with Lewy Bodies, are characterized by widespread accumulation of intracellular alpha-Synuclein protein deposits in regions beyond the brainstem, including in the cortex. However, the impact of local pathology in the cortex is unknown. To investigate this, we employed viral overexpression of human alpha-Synuclein protein targeting the mouse prefrontal cortex (PFC). We then used in vivo 2-photon microscopy to image awake head-fixed mice via an implanted chronic cranial window to assess the early consequences of alpha-Synuclein overexpression in the weeks following overexpression. We imaged apical tufts of Layer V pyramidal neurons in the PFC of Thy1-YFP transgenic mice at 1-week intervals from 1 to 2 weeks before and 9 weeks following viral overexpression, allowing analysis of dynamic changes in dendritic spines. We found an increase in the relative dendritic spine density following local overexpression of alpha-Synuclein, beginning at 5 weeks post-injection, and persisting for the remainder of the study. We found that alpha-Synuclein overexpression led to an increased percentage and longevity of newly-persistent spines, without significant changes in the total density of newly formed or eliminated spines. A follow-up study utilizing confocal microscopy revealed that the increased spine density is found in cortical cells within the alpha-Synuclein injection site, but negative for alpha-Synuclein phosphorylation at Serine-129, highlighting the potential for effects of dose and local circuits on spine survival. These findings have important implications for the physiological role and early pathological stages of alpha-Synuclein in the cortex.


Assuntos
Espinhas Dendríticas , Camundongos Transgênicos , Córtex Pré-Frontal , alfa-Sinucleína , Animais , Humanos , Masculino , Camundongos , alfa-Sinucleína/metabolismo , Sobrevivência Celular/fisiologia , Espinhas Dendríticas/metabolismo , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Células Piramidais/metabolismo , Células Piramidais/patologia
15.
FASEB J ; 37(7): e23017, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37272890

RESUMO

Cell-to-cell spreading of misfolded α-synuclein (αSYN) is supposed to play a key role in the pathological progression of Parkinson's disease (PD) and other synucleinopathies. Receptor-mediated endocytosis has been shown to contributes to the uptake of αSYN in both neuronal and glial cells. To determine the receptor involved in αSYN endocytosis on the cell surface, we performed unbiased, and comprehensive screening using a membrane protein library of the mouse whole brain combined with affinity chromatography and mass spectrometry. The candidate molecules hit in the initial screening were validated by co-immunoprecipitation using cultured cells; sortilin, a vacuolar protein sorting 10 protein family sorting receptor, exhibited the strongest binding to αSYN fibrils. Notably, the intracellular uptake of fibrillar αSYN was slightly but significantly altered, depending on the expression level of sortilin on the cell surface, and time-lapse image analyses revealed the concomitant internalization and endosomal sorting of αSYN fibrils and sortilin. Domain deletion in the extracellular portion of sortilin revealed that the ten conserved cysteines (10CC) segment of sortilin was involved in the binding and endocytosis of fibrillar αSYN; importantly, pretreatment with a 10CC domain-specific antibody significantly hindered αSYN fibril uptake. The presence of sortilin in the core structure of Lewy bodies and glial cytoplasmic inclusions in the brain of synucleinopathy patients was confirmed via immunohistochemistry, and the expression level of sortilin in mesencephalic dopaminergic neurons may be altered with disease progression. These results provide compelling evidence that sortilin acts as an endocytic receptor for pathogenic form of αSYN, and yields important insight for the development of disease-modifying targets for synucleinopathies.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular , Doença de Parkinson , Sinucleinopatias , Animais , Camundongos , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , alfa-Sinucleína/metabolismo , Proteínas de Transporte , Doença de Parkinson/metabolismo
16.
J Sleep Res ; : e14351, 2024 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-39322419

RESUMO

Previous studies indicated that patients with isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) exhibit alterations in spectral electroencephalographic (EEG), spindle, and slow-wave features. As it is currently unknown how these EEG features evolve over time, this study aimed to evaluate their temporal progression in patients with iRBD in comparison to controls. We included 23 patients with iRBD and 23 controls. Two polysomnographies (baseline and follow-up) were recorded with a mean (standard deviation) interval of 4.0 (2.5) years and were automatically analysed for sleep stages, spectral bandpower, spindles, and slow waves. We used linear models to evaluate differences at each time point, and linear mixed-effects models to analyse differences in temporal progression between the groups. At baseline, patients with iRBD presented EEG slowing both in REM (expressed as significantly reduced α-bandpower and increased δ-bandpower in frontal channels) and in non-REM (NREM) sleep (significantly increased slow-to-fast ratio in central channels). These differences vanished at follow-up. In both REM and NREM sleep, γ-bandpower was increased at follow-up in patients with iRBD, resulting in significantly different temporal progression between groups (in occipital channels during REM sleep and frontal channels during NREM sleep). Relative power of sleep spindles was significantly higher at baseline in patients with iRBD in frontal channels, but we observed a significant reduction over time in central channels. Finally, slow waves were significantly shorter in patients with iRBD at both time-points. Our results underscore the need of considering longitudinal data when analysing sleep EEG features in patients with iRBD. The observed temporal changes as markers of progression of neurodegeneration require further investigations.

17.
J Sleep Res ; : e14263, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867555

RESUMO

Several brainstem, subcortical and cortical areas are involved in the generation of rapid eye movement (REM) sleep. The alteration of these structures as a result of a neurodegenerative process may therefore lead to REM sleep anomalies. REM sleep behaviour disorder is associated with nightmares, dream-enacting behaviours and increased electromyographic activity in REM sleep. Its isolated form is a harbinger of synucleinopathies such as Parkinson's disease or dementia with Lewy bodies, and neuroprotective interventions are advocated. This link might also be present in patients taking antidepressants, with post-traumatic stress disorder, or with a history of repeated traumatic head injury. REM sleep likely contributes to normal memory processes. Its alteration has also been proposed to be part of the neuropathological changes occurring in Alzheimer's disease.

18.
J Sleep Res ; : e14204, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38586895

RESUMO

Accumulating evidence indicates that patients with isolated rapid eye movement sleep behaviour disorder (iRBD), a prodromal stage of synucleinopathies, show abnormal deposition of misfolded alpha-synuclein (a-Syn) in peripheral tissues. The clinical utility of testing for a-Syn in iRBD is unclear. This meta-analysis focused on the utility of testing for the abnormal a-Syn phosphorylated at Ser129 (p-syn) and a-Syn seeding activity (a-Syn seed amplification assays [aSyn-SAA]). Following an electronic database search, 15 studies were included that provided at a minimum data on test positivity in participants with iRBD. Test positivity from cerebrospinal fluid (CSF) was 80% (95% confidence interval [CI] 68-88%, I2 = 71%) and for skin was 74.8% (95% CI 53.2-88.5%, I2 = 64%) for aSyn-SAA and 78.5% (95% CI 70.4-84.9%, I2 = 14%) for p-syn. The phenoconversion rate ratio of biopsy-positive versus biopsy-negative iRBD was 1.28 (95% CI 0.68-2.41, I2 = 0%). Skin as a source had a specificity of 99% (95% CI 95-100%, I2 = 0%; p = 0.01 compared to CSF). As a test, p-syn, had a specificity of 100% (95% CI 93-100%, I2 = 0%; p < 0.001) compared to aSyn-SAA. The odds ratio of a-Syn test positivity in iRBD versus other RBDs was 112 (95% CI 20-629, I2 = 0%). These results demonstrate clinically significant test positivity in iRBD and favour skin over CSF as the source of a-Syn pathological analysis, and p-syn over aSyn-SAA as the testing method. Overall, these findings indicate that testing for a-Syn could help in differentiating iRBD from RBD secondary to other conditions.

19.
J Pharmacol Sci ; 156(2): 102-114, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39179329

RESUMO

Synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders characterized by the aberrant accumulation of α-synuclein (α-syn). Although no treatment is effective for synucleinopathies, the suppression of α-syn aggregation may contribute to the development of numerous novel therapeutic targets. Recent research revealed that nicotinic acetylcholine (nACh) receptor activation has neuroprotective effects and promotes the degradation of amyloid protein by activating autophagy. In an in vitro human-derived cell line model, we demonstrated that galantamine, the nAChR allosteric potentiating ligand, significantly reduced the cell number of SH-SY5Y cells with intracellular Lewy body-like aggregates by enhancing the sensitivity of α7-nAChR. In addition, galantamine promoted autophagic flux, and prevented the formation of Lewy body-resembled aggregates. In an in vivo synucleinopathy mouse model, the propagation of α-syn aggregation in the cerebral cortex was inhibited by galantamine administration for 90 days. These results suggest that α7-nAChR is expected to be a novel therapeutic target, and galantamine is a potential agent for synucleinopathies.


Assuntos
Autofagia , Galantamina , alfa-Sinucleína , Receptor Nicotínico de Acetilcolina alfa7 , Galantamina/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , alfa-Sinucleína/metabolismo , Humanos , Autofagia/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Sinucleinopatias/tratamento farmacológico , Sinucleinopatias/metabolismo , Fármacos Neuroprotetores/farmacologia , Masculino , Camundongos , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/tratamento farmacológico , Camundongos Endogâmicos C57BL
20.
Brain ; 146(1): 237-251, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-35170728

RESUMO

Multiple system atrophy is a progressive neurodegenerative disease with prominent autonomic and motor features. During early stages, different subtypes of the disease are distinguished by their predominant parkinsonian or cerebellar symptoms, reflecting its heterogeneous nature. The pathognomonic feature of multiple system atrophy is the presence of α-synuclein (αSyn) protein deposits in oligodendroglial cells. αSyn can assemble in specific cellular or disease environments and form αSyn strains with unique structural features, but the ability of αSyn strains to propagate in oligodendrocytes remains elusive. Recently, it was shown that αSyn strains with related conformations exist in the brains of patients. Here, we investigated whether different αSyn strains can influence multiple system atrophy progression in a strain-dependent manner. To this aim, we injected two recombinant αSyn strains (fibrils and ribbons) in multiple system atrophy transgenic mice and found that they determined disease severity in multiple system atrophy via host-restricted and cell-specific pathology in vivo. αSyn strains significantly impact disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of αSyn strains both in vitro and in vivo. Spectral analysis showed that ribbons propagated oligodendroglial inclusions that were structurally distinct from those of fibrils, with resemblance to oligodendroglial inclusions, in the brains of patients with multiple system atrophy. This study, therefore, shows that the multiple system atrophy phenotype is governed by both the nature of the αSyn strain and the host environment and that by injecting αSyn strains into an animal model of the disease, a more comprehensive phenotype can be established.


Assuntos
Atrofia de Múltiplos Sistemas , alfa-Sinucleína , Camundongos , Animais , alfa-Sinucleína/metabolismo , Atrofia de Múltiplos Sistemas/patologia , Modelos Animais de Doenças , Camundongos Transgênicos , Gravidade do Paciente , Encéfalo/patologia
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