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1.
Cell Mol Life Sci ; 81(1): 75, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38315424

RESUMO

Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (LBDs), including Parkinson's disease (PD), Parkinson's disease-dementia (PDD), and dementia with Lewy bodies (DLB). Nevertheless, there is little mechanistic insight into the role of LRP10 in disease pathogenesis. In the brains of control individuals, LRP10 is typically expressed in non-neuronal cells like astrocytes and neurovasculature, but in idiopathic and genetic cases of PD, PDD, and DLB, it is also present in α-synuclein-positive neuronal Lewy bodies. These observations raise the questions of what leads to the accumulation of LRP10 in Lewy bodies and whether a possible interaction between LRP10 and α-synuclein plays a role in disease pathogenesis. Here, we demonstrate that wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be internalised via clathrin-dependent endocytosis. Additionally, we show that LRP10 secretion is highly sensitive to autophagy inhibition, which induces the formation of atypical LRP10 vesicular structures in neurons in human-induced pluripotent stem cells (iPSC)-derived brain organoids. Furthermore, we show that LRP10 overexpression leads to a strong induction of monomeric α-synuclein secretion, together with time-dependent, stress-sensitive changes in intracellular α-synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424 + 5G > A LRP10 variant secrete aberrant high-molecular-weight species of LRP10 in EV-free media fractions. Finally, we show that this truncated patient-derived LRP10 protein species (LRP10splice) binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonises the effect of LRP10 on α-synuclein levels and distribution. Together, this work provides initial evidence for a possible functional role of LRP10 in LBDs by modulating intra- and extracellular α-synuclein levels, and pathogenic mechanisms linked to the disease-associated c.1424 + 5G > A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs.


Assuntos
Doença por Corpos de Lewy , Doença de Parkinson , Humanos , alfa-Sinucleína/metabolismo , Doença de Parkinson/patologia , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Corpos de Lewy/metabolismo , Encéfalo/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo
2.
Acta Neuropathol ; 147(1): 67, 2024 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-38581586

RESUMO

Transcription factor EB (TFEB) is a master regulator of genes involved in the maintenance of autophagic and lysosomal homeostasis, processes which have been implicated in the pathogenesis of GBA-related and sporadic Parkinson's disease (PD), and dementia with Lewy bodies (DLB). TFEB activation results in its translocation from the cytosol to the nucleus. Here, we investigated TFEB subcellular localization and its relation to intracellular alpha-synuclein (aSyn) accumulation in post-mortem human brain of individuals with either incidental Lewy body disease (iLBD), GBA-related PD/DLB (GBA-PD/DLB) or sporadic PD/DLB (sPD/DLB), compared to control subjects. We analyzed nigral dopaminergic neurons using high-resolution confocal and stimulated emission depletion (STED) microscopy and semi-quantitatively scored the TFEB subcellular localization patterns. We observed reduced nuclear TFEB immunoreactivity in PD/DLB patients compared to controls, both in sporadic and GBA-related cases, as well as in iLBD cases. Nuclear depletion of TFEB was more pronounced in neurons with Ser129-phosphorylated (pSer129) aSyn accumulation in all groups. Importantly, we observed previously-unidentified TFEB-immunopositive perinuclear clusters in human dopaminergic neurons, which localized at the Golgi apparatus. These TFEB clusters were more frequently observed and more severe in iLBD, sPD/DLB and GBA-PD/DLB compared to controls, particularly in pSer129 aSyn-positive neurons, but also in neurons lacking detectable aSyn accumulation. In aSyn-negative cells, cytoplasmic TFEB clusters were more frequently observed in GBA-PD/DLB and iLBD patients, and correlated with reduced GBA enzymatic activity as well as increased Braak LB stage. Altered TFEB distribution was accompanied by a reduction in overall mRNA expression levels of selected TFEB-regulated genes, indicating a possible early dysfunction of lysosomal regulation. Overall, we observed cytoplasmic TFEB retention and accumulation at the Golgi in cells without apparent pSer129 aSyn accumulation in iLBD and PD/DLB patients. This suggests potential TFEB impairment at the early stages of cellular disease and underscores TFEB as a promising therapeutic target for synucleinopathies.


Assuntos
Doença por Corpos de Lewy , Humanos , alfa-Sinucleína/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Encéfalo/patologia , Neurônios Dopaminérgicos/metabolismo , Corpos de Lewy/patologia , Doença por Corpos de Lewy/patologia
3.
Int J Mol Sci ; 24(12)2023 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-37373401

RESUMO

Lewy body diseases (LBD) are pathologically defined as the accumulation of Lewy bodies composed of an aggregation of α-synuclein (αSyn). In LBD, not only the sole aggregation of αSyn but also the co-aggregation of amyloidogenic proteins, such as amyloid-ß (Aß) and tau, has been reported. In this review, the pathophysiology of co-aggregation of αSyn, Aß, and tau protein and the advancement in imaging and fluid biomarkers that can detect αSyn and co-occurring Aß and/or tau pathologies are discussed. Additionally, the αSyn-targeted disease-modifying therapies in clinical trials are summarized.


Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Humanos , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/terapia , Doença por Corpos de Lewy/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo
4.
Neurol Sci ; 43(7): 4125-4132, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35312879

RESUMO

OBJECTIVE: Real-time quaking-induced conversion (RT-QuIC) is a novel in vitro acellular seed amplification analysis and has been widely used to detect prion diseases. Due to the similar mechanism of abnormal aggregation of α-synuclein, RT-QuIC has great potential for diagnosing Lewy body diseases. This meta-analysis was performed to evaluate the diagnostic accuracy of RT-QuIC for Lewy body diseases. METHODS: This study followed the PRISMA statement. We searched six databases for relevant studies published until February 20, 2022. Meta-analysis was conducted using RevMan 5.3, Stata 17.0, and Meta-Disc 1.4. Subgroup analyses were performed to explore sources of heterogeneity. RESULTS: A total of 16 studies were included in this study. The pooled sensitivity and specificity were 0.91 (95%CI: 0.85-0.94) and 0.95 (95%CI: 0.90-0.97), respectively. The pooled positive and negative likelihood ratios were 17.16 (95% CI: 9.16-32.14) and 0.10 (95% CI: 0.06-0.17), respectively. The pooled diagnostic odds rate and area under the summary receiver operating characteristic curve were 171.16 (95% CI: 66.64-439.62) and 0.97 (95% CI: 0.96-0.99), respectively. CONCLUSIONS: This study was the first meta-analysis on RT-QuIC for Lewy body diseases. RT-QuIC is a reliable and accurate method to diagnose Lewy body diseases.


Assuntos
Corpos de Lewy , Doença por Corpos de Lewy , Bioensaio/métodos , Humanos , Doença por Corpos de Lewy/diagnóstico , Sensibilidade e Especificidade
5.
Neurobiol Dis ; 149: 105225, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33347974

RESUMO

Neurodegenerative disorders such as Alzheimer's disease (AD), Lewy body diseases (LBD), and the amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) spectrum are defined by the accumulation of specific misfolded protein aggregates. However, the mechanisms by which each proteinopathy leads to neurodegeneration remain elusive. We hypothesized that there is a common "pan-neurodegenerative" gene expression signature driving pathophysiology across these clinically and pathologically diverse proteinopathies. To test this hypothesis, we performed a systematic review of human CNS transcriptomics datasets from AD, LBD, and ALS-FTD patients and age-matched controls in the Gene Expression Omnibus (GEO) and ArrayExpress databases, followed by consistent processing of each dataset, meta-analysis, pathway enrichment, and overlap analyses. After applying pre-specified eligibility criteria and stringent data pre-processing, a total of 2600 samples from 26 AD, 21 LBD, and 13 ALS-FTD datasets were included in the meta-analysis. The pan-neurodegenerative gene signature is characterized by an upregulation of innate immunity, cytoskeleton, and transcription and RNA processing genes, and a downregulation of the mitochondrial electron transport chain. Pathway enrichment analyses also revealed the upregulation of neuroinflammation (including Toll-like receptor, TNF, and NFκB signaling) and phagocytosis, and the downregulation of mitochondrial oxidative phosphorylation, lysosomal acidification, and ubiquitin-proteasome pathways. Our findings suggest that neuroinflammation and a failure in both neuronal energy metabolism and protein degradation systems are consistent features underlying neurodegenerative diseases, despite differences in the extent of neuronal loss and brain regions involved.


Assuntos
Encéfalo/metabolismo , Metabolismo Energético/fisiologia , Mediadores da Inflamação/metabolismo , Doenças Neurodegenerativas/metabolismo , Proteostase/fisiologia , Transcriptoma/fisiologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Encéfalo/patologia , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia
6.
Acta Neuropathol ; 142(3): 449-474, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34309761

RESUMO

Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular "window" of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.


Assuntos
Perfilação da Expressão Gênica/métodos , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/patologia , Patologia Molecular/métodos , Idoso , Processamento Alternativo , Doença de Alzheimer , Bancos de Espécimes Biológicos , Núcleo Celular/genética , Núcleo Celular/ultraestrutura , Giro do Cíngulo/patologia , Humanos , Corpos de Lewy/patologia , Microglia/patologia , Microglia/ultraestrutura , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/ultraestrutura , Doença de Parkinson , RNA/genética , Transcriptoma
7.
Mov Disord ; 36(8): 1744-1758, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33939203

RESUMO

Intracellular vesicular trafficking is essential for neuronal development, function, and homeostasis and serves to process, direct, and sort proteins, lipids, and other cargo throughout the cell. This intricate system of membrane trafficking between different compartments is tightly orchestrated by Ras analog in brain (RAB) GTPases and their effectors. Of the 66 members of the RAB family in humans, many have been implicated in neurodegenerative diseases and impairment of their functions contributes to cellular stress, protein aggregation, and death. Critically, RAB39B loss-of-function mutations are known to be associated with X-linked intellectual disability and with rare early-onset Parkinson's disease. Moreover, recent studies have highlighted altered RAB39B expression in idiopathic cases of several Lewy body diseases (LBDs). This review contextualizes the role of RAB proteins in LBDs and highlights the consequences of RAB39B impairment in terms of endosomal trafficking, neurite outgrowth, synaptic maturation, autophagy, as well as alpha-synuclein homeostasis. Additionally, the potential for therapeutic intervention is examined via a discussion of the recent progress towards the development of specific RAB modulators. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doença por Corpos de Lewy , Doença de Parkinson , Humanos , Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/genética , Doença de Parkinson/genética , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
8.
J Neurochem ; 152(2): 235-251, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31613384

RESUMO

The striatum with a number of dopamine containing neurons, receiving projections from the substantia nigra and ventral tegmental area; plays a critical role in neurodegenerative diseases of motor and memory function. Additionally, oxidative damage to nucleic acid may be vital in the development of age-associated neurodegeneration. The metabolism of dopamine is recognized as one of the sources of reactive oxygen species through the Fenton mechanism. The proposed interactions of oxidative insults and dopamine in the striatum during the progression of diseases are the hypotheses of most interest to our study. This study investigated the possibility of significant interactions between these molecules that are involved in the late-stage of Alzheimer's disease (AD), Parkinson disease (PD), Parkinson disease dementia, dementia with Lewy bodies, and controls using ELISA assays, autoradiography, and mRNA in situ hybridization assay. Interestingly, lower DNA/RNA oxidative adducts levels in the caudate and putamen of diseased brains were observed with the exception of an increased DNA oxidative product in the caudate of AD brains. Similar changes were found for dopamine concentration and vesicular monoamine transporter 2 densities. We also found that downstream pre-synaptic dopamine D1 Receptor binding correlated with dopamine loss in Lewy body disease groups, and RNA damage and ß-site APP cleaving enzyme 1 in the caudate of AD. This is the first demonstration of region-specific alterations of DNA/RNA oxidative damage which cannot be viewed in isolation, but rather in connection with the interrelationship between different neuronal events; chiefly DNA oxidative adducts and density of vesicular monoamine transporter 2 densities in AD and PD patients.


Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Estresse Oxidativo/fisiologia , Idoso , Idoso de 80 Anos ou mais , Corpo Estriado/patologia , DNA/genética , DNA/metabolismo , Dopamina/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/genética , Ligação Proteica/fisiologia , RNA/genética , RNA/metabolismo
9.
Neurobiol Dis ; 145: 105082, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32927063

RESUMO

Causative genes involved in familial forms of dementias, including Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB), as well as amyotrophic lateral sclerosis and prion diseases where dementia is present as a significant clinical feature, are associated with distinct proteinopathies. This review summarizes the relationship between known genetic determinants of these dementia syndromes and variations in key neuropathological proteins in terms of three types of heterogeneity: (i) Locus Heterogeneity, whereby mutations in different genes cause a similar proteinopathy, as exemplified by mutations in APP, PSEN1 and PSEN2 leading to AD neuropathology; (ii) Allelic Heterogeneity, whereby different mutations in the same gene lead to different proteinopathies or neuropathological severity, as exemplified by different mutations in MAPT and PRNP giving rise to protein species that differ in their biochemistry and affected cell types; and (iii) Phenotypic Heterogeneity, where identical gene mutations lead to different proteinopathies, as exemplified by LRRK2 p.G2019S being associated with variable Lewy body presence and alternative AD neuropathology or FTLD-tau. Of note, the perceived homogeneity in histologic phenotypes may arise from laboratory-specific assessment protocols which can differ in the panel of proteins screened. Finally, the understanding of the complex relationship between genotype and phenotype in dementia families is highly relevant in terms of therapeutic strategies which range from targeting specific genes, to a broader strategy of targeting a downstream, common biochemical problem that leads to the histopathology.


Assuntos
Demência/genética , Demência/patologia , Estudos de Associação Genética , Humanos
10.
Neuropathol Appl Neurobiol ; 46(7): 707-721, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32892355

RESUMO

AIMS: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aß) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing. METHODS: Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aß. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing. RESULTS: LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aß severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009). CONCLUSIONS: Our findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Hipocampo/patologia , Doença por Corpos de Lewy/patologia , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Córtex Entorrinal/metabolismo , Feminino , Humanos , Masculino , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo
11.
Int J Mol Sci ; 21(17)2020 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-32842621

RESUMO

We found interactions between dopamine and oxidative damage in the striatum involved in advanced neurodegeneration, which probably change the microglial phenotype. We observed possible microglia dystrophy in the striatum of neurodegenerative brains. To investigate the interactions between oxidative damage and microglial phenotype, we quantified myeloperoxidase (MPO), poly (ADP-Ribose) (PAR), and triggering receptors expressed on myeloid cell 2 (TREM2) using enzyme-linked immunosorbent assay (ELISA). To test the correlations of microglia dystrophy and tauopathy, we quantified translocator protein (TSPO) and tau fibrils using autoradiography. We chose the caudate and putamen of Lewy body diseases (LBDs) (Parkinson's disease, Parkinson's disease dementia, and Dementia with Lewy body), Alzheimer's disease (AD), and control brains and genotyped for TSPO, TREM2, and bridging integrator 1 (BIN1) genes using single nucleotide polymorphisms (SNP) assays. TREM2 gene variants were absent across all samples. However, associations between TSPO and BIN1 gene polymorphisms and TSPO, MPO, TREM2, and PAR level variations were found. PAR levels reduced significantly in the caudate of LBDs. TSPO density and tau fibrils decreased remarkably in the striatum of LBDs but increased in AD. Oxidative damage, induced by misfolded tau proteins and dopamine metabolism, causes microglia dystrophy or senescence during the late stage of LBDs. Consequently, microglia dysfunction conversely reduces tau propagation. The G allele of the BIN1 gene is a potential risk factor for tauopathy.


Assuntos
Corpo Estriado/metabolismo , Microglia/patologia , Doenças Neurodegenerativas/patologia , Tauopatias/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Estudos de Casos e Controles , Corpo Estriado/patologia , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Microglia/fisiologia , Pessoa de Meia-Idade , Doenças Neurodegenerativas/genética , Proteínas Nucleares/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Peroxidase/metabolismo , Poli Adenosina Difosfato Ribose/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores de GABA/genética , Receptores de GABA/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Tauopatias/genética , Proteínas Supressoras de Tumor/genética , Proteínas tau/metabolismo
12.
Int J Mol Sci ; 21(13)2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32630630

RESUMO

Lewy body disorders (LBD) include Parkinson's disease (PD) and dementia with Lewy bodies (DLB). They are synucleinopathies with a heterogeneous clinical manifestation. As a cause of neuropathological overlap with other neurodegenerative diseases, the establishment of a correct clinical diagnosis is still challenging, and clinical management may be difficult. The combination of genetic variation and epigenetic changes comprising gene expression-modulating DNA methylation and histone alterations modifies the phenotype, disease course, and susceptibility to disease. In this review, we summarize the results achieved in the deciphering of the LBD epigenome. To provide an appropriate context, first LBD genetics is briefly outlined. Afterwards, a detailed review of epigenetic modifications identified for LBD in human cells, postmortem, and peripheral tissues is provided. We also focus on the difficulty of identifying epigenome-related biomarker candidates and discuss the results obtained so far. Additionally, epigenetic changes as therapeutic targets, as well as different epigenome-based treatments, are revised. The number of studies focusing on PD is relatively limited and practically inexistent for DLB. There is a lack of replication studies, and some results are even contradictory, probably due to differences in sample collection and analytical techniques. In summary, we show the current achievements and directions for future research.


Assuntos
Epigênese Genética/genética , Corpos de Lewy/genética , Doença por Corpos de Lewy/genética , Biomarcadores , Demência/genética , Progressão da Doença , Epigênese Genética/fisiologia , Epigenômica/métodos , Expressão Gênica/genética , Humanos , Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Doenças Neurodegenerativas/genética , Doença de Parkinson/patologia
13.
Acta Neuropathol ; 138(5): 771-782, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31494694

RESUMO

According to a generally accepted concept Lewy-related pathology (LRP) follows hierarchical caudo-rostral progression. LRP is also frequently present concomitantly with Alzheimer's disease (AD), and it has been hypothesized that AD-associated LRP forms a distinct type of α-synucleinopathy, where LRP originates in the amygdala. The frequency of distinct forms of LRP progression types has not been studied in a population-based setting. We investigated the distribution and progression of LRP and its relation to AD pathology and apolipoprotein (APOE) ε4 in a population-based sample of Finns aged over 85 years (N = 304). Samples from spinal cord to neocortical areas representing 11 anatomical sites without any hierarchical selection were analyzed immunohistochemically (α-synuclein antibody clone 5G4). LRP was present in 124 individuals (41%) and according to DLB Consortium guidelines 19 of them were categorized as brainstem, 10 amygdala-predominant, 41 limbic, and 43 diffuse neocortical type, whereas 11 could not be classified. To determine the LRP progression patterns, a systematic anatomical scoring was carried out by taking into account the densities of the semiquantitative LRP scores in each anatomic site. With this scoring 123 (99%) subjects could be classified into two progression pattern types: 67% showed caudo-rostral and 32% amygdala-based progression. The unsupervised statistical K-means cluster analysis was used as a supplementary test and supported the presence of two progression patterns and had a 90% overall concordance with the systematic anatomical scoring method. Severe Braak NFT stage, high CERAD score and APOE ε4 were significantly (all p < 0.00001) associated with amygdala-based, but not with caudo-rostral progression type (all p > 0.2). This population-based study demonstrates two distinct common LRP progression patterns in the very elderly population. The amygdala-based pattern was associated with APOE ε4 and AD pathology. The results confirm the previous progression hypotheses but also widen the concept of the AD-associated LRP.


Assuntos
Doença de Alzheimer/patologia , Corpos de Lewy/patologia , Doença por Corpos de Lewy/patologia , Doença de Parkinson/patologia , Idoso de 80 Anos ou mais , Encéfalo/patologia , Progressão da Doença , Feminino , Humanos , Masculino
15.
Brain Commun ; 6(4): fcae190, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38978726

RESUMO

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

16.
medRxiv ; 2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37987016

RESUMO

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be key to understanding disease pathways and ultimately therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7,804 patients of European ancestry from Tracking Parkinson's (PRoBaND), The Oxford Discovery Cohort, and AMP-PD. We conducted a discrete phenotype genome-wide association studies comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk alleles rs429358 tagging APOEe4 and rs7668531 near the MMRN1 and SNCA-AS1 genes, increase the odds of developing dementia and that an intronic variant rs17442721 tagging LRRK2 G2019S, on chromosome 12 is protective against dementia. These results should be validated in autopsy confirmed cases in future studies.

17.
Dis Model Mech ; 15(1)2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34842277

RESUMO

Recent reports indicate that Parkinson's disease (PD) involves specific functional abnormalities in residual neurons - decreased vesicular sequestration of cytoplasmic catecholamines via the vesicular monoamine transporter (VMAT) and decreased aldehyde dehydrogenase (ALDH) activity. This double hit builds up the autotoxic metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), the focus of the catecholaldehyde hypothesis for the pathogenesis of PD. An animal model is needed that reproduces this abnormal catecholamine neurochemical pattern. Adult rats received subcutaneous vehicle or the mitochondrial complex 1 inhibitor rotenone (2 mg/kg/day via a minipump) for 10 days. Locomotor activity was recorded, and striatal tissue sampled for catechol contents and catechol ratios that indicate the above abnormalities. Compared to vehicle, rotenone reduced locomotor activity (P=0.002), decreased tissue dopamine concentrations (P=0.00001), reduced indices of vesicular sequestration (3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine) and ALDH activity (DOPAC/DOPAL) (P=0.0025, P=0.036), and increased DOPAL levels (P=0.04). The rat rotenone model involves functional abnormalities in catecholaminergic neurons that replicate the pattern found in PD putamen. These include a vesicular storage defect, decreased ALDH activity and DOPAL build-up. The rat rotenone model provides a suitable in vivo platform for studying the catecholaldehyde hypothesis.


Assuntos
Doença de Parkinson , Rotenona , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Catecolaminas , Dopamina/metabolismo , Doença de Parkinson/patologia , Ratos , Rotenona/farmacologia
18.
Neural Regen Res ; 17(4): 867-874, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34472487

RESUMO

Neurodegenerative diseases are a class of chronic and complex disorders featuring progressive loss of neurons in distinct brain areas. The mechanisms responsible for the disease progression in neurodegeneration are not fully illustrated. In this observational study, we have examined diverse biochemical parameters in the caudate and putamen of patients with Lewy body diseases (LBDs) and Alzheimer disease (AD), shedding some light on the involvement of oxidative damage and neuroinflammation in advanced neurodegeneration. We performed Spearman and Mantel-Cox analyses to investigate how oxidative stress and neuroinflammation exert comprehensive effects on disease progression and survival. Disease progression in LBDs correlated positively with poly (ADP-Ribose) and triggering receptors expressed on myeloid cell 2 levels in the striatum of LBD cohorts, indicating that potential parthanatos was a dominant feature of worsening disease progression and might contribute to switching microglial inflammatory phenotypes. Disease progression in AD corresponds negatively with 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and myeloperoxidase concentrations in the striatum, suggesting that possible mitochondria dysfunction may be involved in the progression of AD via a mechanism of ß-amyloid entering the mitochondria and subsequent free radicals generation. Patients with lower striatal 8-oxo-dG and myeloperoxidase levels had a survival advantage in AD. The age of onset also affected disease progression. Tissue requests for the postmortem biochemistry, genetics, and autoradiography studies were approved by the Washington University Alzheimer's Disease Research Center (ADRC) Biospecimens Committee (ethics approval reference number: T1705, approval date: August 6, 2019). Recombinant DNA and Hazardous Research Materials were approved by the Washington University Environmental Health & Safety Biological Safety Committee (approval code: 3739, approval date: February 25, 2020). Radioactive Material Authorization was approved by the Washington University Environmental Health & Safety Radiation Safety Committee (approval code: 1056, approval date: September 18, 2019).

19.
Brain Sci ; 12(2)2022 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-35203912

RESUMO

The emergence of cognitive impairment and dementia in people with Lewy body spectrum disorders (LBS) significantly impacts the quality of life of the individual and their care partner. Coping well with the condition may depend, in part, on the degree of psychological resilience or capacity to 'bounce back' from adversity. We explored resilience in people with Parkinson's disease mild cognitive disorder or dementia, or dementia with Lewy bodies, and their care partners, and its relation to outcomes related to their mental well-being and quality of life. This exploratory, cross-sectional study recruited 76 participant-dyads. Resilience, quality of life, depression, anxiety, and relationship satisfaction were evaluated in both members of the dyad. In care partners, care burden and stress were also assessed. Over 70% of both care partners and recipients reported high levels of resilience. Lower resilience in both members of the dyad was associated with higher anxiety and lower quality of life. Additionally, lower resilience in care partners was associated with lower well-being, relationship satisfaction, and higher burden and stress. Resilience in persons with LBS and their care partners is important to consider when assessing mental health, relationship, and care burden outcomes, acting as a focus of intervention to support positive outcomes.

20.
Clin Interv Aging ; 17: 467-477, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35431542

RESUMO

Purpose: Idiopathic normal pressure hydrocephalus (iNPH) is the leading reversible cause of cognitive impairment and gait disturbance that has similar clinical manifestations and accompanies to major neurodegenerative disorders in older adults. We aimed to investigate whether cerebrospinal fluid (CSF) biomarker for Alzheimer's disease (AD) may be useful in the differential diagnosis of iNPH. Patients and Methods: Amyloid-beta (Aß) 42 and 40, total tau (t-tau), phosphorylated tau (p-tau) were measured via ELISA in 192 consecutive CSF samples of patients with iNPH (n=80), AD (n=48), frontotemporal dementia (FTD) (n=34), Lewy body diseases (LBDs) (n=30) consisting of Parkinson's disease dementia and dementia with Lewy bodies. Results: The mean age of the study population was 75.6±7.7 years, and 54.2% were female. CSF Aß42 levels were significantly higher, and p-tau and t-tau levels were lower in iNPH patients than in those with AD and LBDs patients. Additionally, iNPH patients had significantly higher levels of t-tau than those with FTD. Age and sex-adjusted multi-nominal regression analysis revealed that the odds of having AD relative to iNPH decreased by 37% when the Aß42 level increased by one standard deviation (SD), and the odds of having LBDs relative to iNPH decreased by 47%. The odds of having LBDs relative to iNPH increased 76% when the p-tau level increased 1SD. It is 2.5 times more likely for a patient to have LBD relative to NPH and 2.1 times more likely to have AD relative to iNPH when the t-tau value increased 1SD. Conclusion: Our results suggest that levels of CSF Aß42, p-tau, and t-tau, in particularly decreased t-tau, are of potential value in differentiating iNPH from LBDs and also confirm previous studies reporting t-tau level is lower and Aß42 level is higher in iNPH than in AD.


Assuntos
Doença de Alzheimer , Demência Frontotemporal , Hidrocefalia de Pressão Normal , Doença por Corpos de Lewy , Doença de Parkinson , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Masculino , Fragmentos de Peptídeos , Proteínas tau/líquido cefalorraquidiano
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