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1.
Arq Neuropsiquiatr ; 79(7): 612-623, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34468500

RESUMO

BACKGROUND: Increasing numbers of mutations causing monogenic forms of Parkinson's disease (PD) have been described, mostly among patients in Europe and North America. Since genetic architecture varies between different populations, studying the specific genetic profile of Brazilian patients is essential for improving genetic counseling and for selecting patients for clinical trials. OBJECTIVE: We conducted a systematic review to identify genetic studies on Brazilian patients and to set a background for future studies on monogenic forms of PD in Brazil. METHODS: We searched MEDLINE, EMBASE and Web of Science from inception to December 2019 using terms for "Parkinson's disease", "genetics" and "Brazil". Two independent reviewers extracted the data. For the genes LRRK2 and PRKN, the estimated prevalence was calculated for each study, and a meta-analysis was performed. RESULTS: A total of 32 studies were included, comprising 94 Brazilian patients with PD with a causative mutation, identified from among 2,872 screened patients (3.2%). PRKN mutations were causative of PD in 48 patients out of 576 (8.3%). LRRK2 mutations were identified in 40 out of 1,556 patients (2.5%), and p.G2019S was the most common mutation (2.2%). CONCLUSIONS: PRKN is the most common autosomal recessive cause of PD, and LRRK2 is the most common autosomal dominant form. We observed that there was a lack of robust epidemiological studies on PD genetics in Brazil and, especially, that the diversity of Brazil's population had not been considered.


Assuntos
Doença de Parkinson , Brasil , Europa (Continente) , Aconselhamento Genético , Predisposição Genética para Doença , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Mutação , Doença de Parkinson/genética
2.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360942

RESUMO

The exact mechanism underlying selective dopaminergic neurodegeneration is not completely understood. The complex interplay among toxic alpha-synuclein aggregates, oxidative stress, altered intracellular Ca2+-homeostasis, mitochondrial dysfunction and disruption of mitochondrial integrity is considered among the pathogenic mechanisms leading to dopaminergic neuronal loss. We herein investigated the molecular mechanisms leading to mitochondrial dysfunction and its relationship with activation of the neuroinflammatory process occurring in Parkinson's disease. To address these issues, experiments were performed in vitro and in vivo in mice carrying the human mutation of α-synuclein A53T under the prion murine promoter. In these models, the expression and activity of NCX isoforms, a family of important transporters regulating ionic homeostasis in mammalian cells working in a bidirectional way, were evaluated in neurons and glial cells. Mitochondrial function was monitored with confocal microscopy and fluorescent dyes to measure mitochondrial calcium content and mitochondrial membrane potential. Parallel experiments were performed in 4 and 16-month-old A53T-α-synuclein Tg mice to correlate the functional data obtained in vitro with mitochondrial dysfunction and neuroinflammation through biochemical analysis. The results obtained demonstrated: 1. in A53T mice mitochondrial dysfunction occurs early in midbrain and later in striatum; 2. mitochondrial dysfunction occurring in the midbrain is mediated by the impairment of NCX3 protein expression in neurons and astrocytes; 3. mitochondrial dysfunction occurring early in midbrain triggers neuroinflammation later into the striatum, thus contributing to PD progression during mice aging.


Assuntos
Mesencéfalo/metabolismo , Mitocôndrias/metabolismo , Doença de Parkinson/metabolismo , Trocador de Sódio e Cálcio/metabolismo , alfa-Sinucleína/genética , Animais , Astrócitos/metabolismo , Cálcio/metabolismo , Células Cultivadas , Neurônios Dopaminérgicos/metabolismo , Mesencéfalo/citologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Doença de Parkinson/genética , Trocador de Sódio e Cálcio/genética , alfa-Sinucleína/metabolismo
3.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360863

RESUMO

In recent decades, genetic research has nominated promising pathways and biological insights contributing to the etiological landscape of parkinsonism-related dystonias and atypical parkinsonism-related syndromes. Several disease-causing mutations and genetic risk factors have been unraveled, providing a deeper molecular understanding of the complex genetic architecture underlying these conditions. These disorders are difficult to accurately diagnose and categorize, thus making genetics research challenging. On one hand, dystonia is an umbrella term linked to clinically heterogeneous forms of disease including dopa-responsive dystonia, myoclonus-dystonia, rapid-onset dystonia-parkinsonism and dystonia-parkinsonism, often viewed as a precursor to Parkinson's disease. On the other hand, atypical parkinsonism disorders, such as progressive supranuclear palsy, multiple system atrophy and corticobasal degeneration, are rare in nature and represent a wide range of diverse and overlapping phenotypic variabilities, with genetic research limited by sample size availability. The current review summarizes the plethora of available genetic information for these diseases, outlining limits and future directions.


Assuntos
Distonia/genética , Atrofia de Múltiplos Sistemas/genética , Doença de Parkinson/genética , Transtornos Parkinsonianos/genética , Paralisia Supranuclear Progressiva/genética , Humanos
4.
Am J Hum Genet ; 108(9): 1647-1668, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34416157

RESUMO

Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing quantitative trait locus (e/sQTL) analyses is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs, and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors (n = 85) and their sorted neuronal progeny (n = 74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome-wide association, we uncover cell-type-specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations for cortical surface area and educational attainment.


Assuntos
Proteínas Cromossômicas não Histona/genética , Regulação da Expressão Gênica no Desenvolvimento , Neocórtex/metabolismo , Neurogênese/genética , Neurônios/metabolismo , Locos de Características Quantitativas , Alelos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Diferenciação Celular , Cromatina/química , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Mapeamento Cromossômico , Escolaridade , Feminino , Feto , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Neuroticismo , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Cultura Primária de Células , Prognóstico , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Esquizofrenia/metabolismo , Transcriptoma
5.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445784

RESUMO

Neurodegenerative disorders involve the slow and gradual degeneration of axons and neurons in the central nervous system (CNS), resulting in abnormalities in cellular function and eventual cellular demise. Patients with these disorders succumb to the high medical costs and the disruption of their normal lives. Current therapeutics employed for treating these diseases are deemed palliative. Hence, a treatment strategy that targets the disease's cause, not just the symptoms exhibited, is desired. The synergistic use of nanomedicine and gene therapy to effectively target the causative mutated gene/s in the CNS disease progression could provide the much-needed impetus in this battle against these diseases. This review focuses on Parkinson's and Alzheimer's diseases, the gene/s and proteins responsible for the damage and death of neurons, and the importance of nanomedicine as a potential treatment strategy. Multiple genes were identified in this regard, each presenting with various mutations. Hence, genome-wide sequencing is essential for specific treatment in patients. While a cure is yet to be achieved, genomic studies form the basis for creating a highly efficacious nanotherapeutic that can eradicate these dreaded diseases. Thus, nanomedicine can lead the way in helping millions of people worldwide to eventually lead a better life.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/genética , Animais , Humanos , Nanomedicina/métodos , Doenças Neurodegenerativas/genética , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética
6.
Neurol Sci ; 42(10): 4085-4094, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34346015

RESUMO

BACKGROUND AND PURPOSE: Polymorphisms of the catechol-O-methyl transferase (COMT) or monoamine oxidase B (MAO-B) genes may affect the occurrence of dyskinesia in Parkinson's disease (PD) patients. However, the findings are inconsistent. Thus, we performed a meta-analysis to assess whether COMT and MAO-B genetic variants are associated with an increased incidence of levodopa-induced dyskinesia (LID) in PD patients. METHODS: A literature search of PubMed, Embase, and Cochrane Library was conducted to identify relevant studies published up to January 2021. The strength of the association between the polymorphisms and LID susceptibility was estimated by odds ratio (OR) and associated 95% confidence interval (CI). The pooled ORs were assessed in different genetic models. RESULTS: Ten studies involving 2385 PD patients were included in the meta-analysis. Analysis of pooled ORs and 95% CIs suggested that the AA genotype of COMT(rs4680) was associated with LID (OR = 1.39, 95%CI: 1.02-1.89, P = 0.039) in the recessive model, and this correlation was more obvious in Brazilian samples in the analysis stratified by ethnicity. For the AG genotype of MAO-B(rs1799836), the pooled OR was 1.66 (95% CI: 1.04-2.65, P = 0.03) in patients with LID versus those without LID in the heterozygote model. CONCLUSIONS: Our meta-analysis implicates the AA genotype of the COMT rs4680 polymorphism as potentially increasing the risk of LID in a recessive genetic model for PD patients. Furthermore, the AG genotype of the MAO-B rs1799836 polymorphism may influence the prevalence of LID in PD patients in the heterozygote model. However, further well-designed studies with larger PD patient cohorts are required to validate these results after adjusting for confounding factors.


Assuntos
Discinesias , Doença de Parkinson , Catecol O-Metiltransferase/genética , Humanos , Levodopa/efeitos adversos , Monoaminoxidase/genética , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética
7.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199427

RESUMO

The interplay between α-synuclein and dopamine derivatives is associated with oxidative stress-dependent neurodegeneration in Parkinson's disease (PD). The formation in the dopaminergic neurons of intraneuronal inclusions containing aggregates of α-synuclein is a typical hallmark of PD. Even though the biochemical events underlying the aberrant aggregation of α-synuclein are not completely understood, strong evidence correlates this process with the levels of dopamine metabolites. In vitro, 3,4-dihydroxyphenylacetaldehyde (DOPAL) and the other two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET), share the property to inhibit the growth of mature amyloid fibrils of α-synuclein. Although this effect occurs with the formation of differently toxic products, the molecular basis of this inhibition is still unclear. Here, we provide information on the effect of DOPAC on the aggregation properties of α-synuclein and its ability to interact with membranes. DOPAC inhibits α-synuclein aggregation, stabilizing monomer and inducing the formation of dimers and trimers. DOPAC-induced oligomers did not undergo conformational transition in the presence of membranes, and penetrated the cell, where they triggered autophagic processes. Cellular assays showed that DOPAC reduced cytotoxicity and ROS production induced by α-synuclein aggregates. Our findings show that the early radicals resulting from DOPAC autoxidation produced covalent modifications of the protein, which were not by themselves a primary cause of either fibrillation or membrane binding inhibition. These findings are discussed in the light of the potential mechanism of DOPAC protection against the toxicity of α-synuclein aggregates to better understand protein and catecholamine biology and to eventually suggest a scaffold that can help in the design of candidate molecules able to interfere in α-synuclein aggregation.


Assuntos
Proliferação de Células/efeitos dos fármacos , Doença de Parkinson/genética , Agregação Patológica de Proteínas/genética , alfa-Sinucleína/genética , Ácido 3,4-Di-Hidroxifenilacético/análogos & derivados , Ácido 3,4-Di-Hidroxifenilacético/farmacologia , Amiloide/efeitos dos fármacos , Amiloide/genética , Dopamina/genética , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Humanos , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Agregação Patológica de Proteínas/tratamento farmacológico , Multimerização Proteica/genética , alfa-Sinucleína/antagonistas & inibidores
8.
Zool Res ; 42(4): 469-477, 2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34213093

RESUMO

Mutations of PTEN-induced kinase I (PINK1) cause early-onset Parkinson's disease (PD) with selective neurodegeneration in humans. However, current PINK1 knockout mouse and pig models are unable to recapitulate the typical neurodegenerative phenotypes observed in PD patients. This suggests that generating PINK1 disease models in non-human primates (NHPs) that are close to humans is essential to investigate the unique function of PINK1 in primate brains. Paired single guide RNA (sgRNA)/Cas9-D10A nickases and truncated sgRNA/Cas9, both of which can reduce off-target effects without compromising on-target editing, are two optimized strategies in the CRISPR/Cas9 system for establishing disease animal models. Here, we combined the two strategies and injected Cas9-D10A mRNA and two truncated sgRNAs into one-cell-stage cynomolgus zygotes to target the PINK1 gene. We achieved precise and efficient gene editing of the target site in three newborn cynomolgus monkeys. The frame shift mutations of PINK1 in mutant fibroblasts led to a reduction in mRNA. However, western blotting and immunofluorescence staining confirmed the PINK1 protein levels were comparable to that in wild-type fibroblasts. We further reprogramed mutant fibroblasts into induced pluripotent stem cells (iPSCs), which showed similar ability to differentiate into dopamine (DA) neurons. Taken together, our results showed that co-injection of Cas9-D10A nickase mRNA and sgRNA into one-cell-stage cynomolgus embryos enabled the generation of human disease models in NHPs and target editing by pair truncated sgRNA/Cas9-D10A in PINK1 gene exon 2 did not impact protein expression.


Assuntos
Modelos Animais de Doenças , Macaca fascicularis/genética , Doença de Parkinson/veterinária , Proteínas Quinases/metabolismo , Animais , Animais Recém-Nascidos , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/metabolismo , Técnicas de Cultura Embrionária , Transferência Embrionária , Fibroblastos/fisiologia , Mutação da Fase de Leitura , Regulação da Expressão Gênica , Macaca fascicularis/embriologia , Doenças dos Macacos/genética , Mutação , Doença de Parkinson/genética , Proteínas Quinases/genética , RNA Guia
11.
Genes (Basel) ; 12(6)2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205689

RESUMO

Accumulation of α-Synuclein (αSyn) in nigral dopaminergic neurons is commonly seen in patients with Parkinson's disease (PD). We recently reported that transduction of intracellular single-chain intrabody targeting the 53-87 amino acid residues of human αSyn by recombinant adeno associated viral vector (AAV-NAC32) downregulated αSyn protein in SH-SY5Y cells and rat brain. This study characterizes the behavioral phenotype and dopaminergic protection in animals receiving AAV-NAC32. Our results show that adult DAT-Cre rats selectively overexpress αSyn in nigra dopaminergic neurons after local administration of AAV-DIO-αSyn. These animals develop PD-like phenotype, including bradykinesia and loss of tyrosine hydroxylase (TH) immunoreactivity in substantia nigra pars compacta dorsal tier (SNcd). An injection of AAV-NAC32 to nigra produces a selective antibody against αSyn and normalizes the behavior. AAV-NAC32 significantly increases TH, while reduces αSyn immunoreactivity in SNcd. Altogether, our data suggest that an AAV-mediated gene transfer of NAC32 antibody effectively antagonizes αSyn-mediated dopaminergic degeneration in nigra, which may be a promising therapeutic candidate for synucleinopathy or PD.


Assuntos
Anticorpos/uso terapêutico , Imunoterapia/métodos , Locomoção , Doença de Parkinson/terapia , alfa-Sinucleína/imunologia , Animais , Anticorpos/imunologia , Células CHO , Cricetinae , Cricetulus , Dependovirus/genética , Neurônios Dopaminérgicos/metabolismo , Vetores Genéticos/genética , Masculino , Doença de Parkinson/genética , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Ratos , Ratos Long-Evans , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , alfa-Sinucleína/química , alfa-Sinucleína/genética
12.
Neurol Sci ; 42(10): 4007-4015, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34254198

RESUMO

Parkinson's disease (PD) is known as one of the most common degenerative disorders related to the damage of the central nervous system (CNS). This brain disorder is also characterized by the formation of Lewy bodies in the cytoplasm of the dopaminergic neurons in the substantia nigra pars compacta (SNc), which consequently leads to motor and non-motor symptoms. With regard to the growing trend in the number of cases with PD and its effects on individuals, families, and communities, immediate treatments together with diagnostic methods are required. In this respect, long non-coding ribonucleic acids (lncRNAs) represent a large class of ncRNAs with more than 200 nucleotides in length, playing key roles in some important processes including gene expression, cell differentiation, genomic imprinting, apoptosis, and cell cycle. They are highly expressed in the CNS and previous studies have further reported that the expression profile of lncRNAs is disrupted in human diseases such as neurodegenerative disorders. Since the levels of some lncRNAs change over time in the brains of patients with PD, a number of previous studies have examined their potentials as biomarkers for this brain disorder. Therefore, the main purpose of this study was to review the advances in the related literature on lncRNAs as diagnostic, therapeutic, and prognostic biomarkers for PD.


Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , RNA Longo não Codificante , Biomarcadores , Neurônios Dopaminérgicos , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Doença de Parkinson/terapia , RNA Longo não Codificante/genética
13.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203739

RESUMO

It is without any doubt that precision medicine therapeutic strategies targeting neurodegenerative disorders are currently witnessing the spectacular rise of newly designed approaches based on the use of viral vectors as Trojan horses for the controlled release of a given genetic payload. Among the different types of viral vectors, adeno-associated viruses (AAVs) rank as the ones most commonly used for the purposes of either disease modeling or for therapeutic strategies. Here, we reviewed the current literature dealing with the use of AAVs within the field of Parkinson's disease with the aim to provide neuroscientists with the advice and background required when facing a choice on which AAV might be best suited for addressing a given experimental challenge. Accordingly, here we will be summarizing some insights on different AAV serotypes, and which would be the most appropriate AAV delivery route. Next, the use of AAVs for modeling synucleinopathies is highlighted, providing potential readers with a landscape view of ongoing pre-clinical and clinical initiatives pushing forward AAV-based therapeutic approaches for Parkinson's disease and related synucleinopathies.


Assuntos
Pesquisa Biomédica , Dependovirus/genética , Vetores Genéticos/uso terapêutico , Doença de Parkinson/genética , Animais , Modelos Animais de Doenças , Técnicas de Transferência de Genes , Humanos
14.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206133

RESUMO

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally, DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (αS), a major component of Lewy bodies. DOPAL potently oligomerizes αS, and αS oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward the MAO-catalyzed formation of DOPAL-destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could "freeze" intraneuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with αS, and vice versa, is poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intraneuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.


Assuntos
Catecóis/metabolismo , Dopamina/metabolismo , Degeneração Neural/genética , Doença de Parkinson/genética , Aldeído Desidrogenase/genética , Aldeídos/metabolismo , Animais , Humanos , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/uso terapêutico , Degeneração Neural/patologia , Neurônios/metabolismo , Neurônios/patologia , Oxirredução , Células PC12 , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Ratos , alfa-Sinucleína/genética
15.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204806

RESUMO

Transposable elements (TEs) are repetitive elements that belong to a variety of functional classes and have an important role in shaping genome evolution. Around 50% of the human genome contains TEs, and they have been termed the "dark matter" of the genome because relatively little is known about their function. While TEs have been shown to participate in aberrant gene regulation and the pathogenesis of diseases, only a few studies have explored the systemic effect of TEs on gene expression. In the present study, we analysed whole genome sequences and blood whole transcriptome data from 570 individuals within the Parkinson's Progressive Markers Initiative (PPMI) cohort to identify expression quantitative trait loci (eQTL) regulating genome-wide gene expression associated with TEs. We identified 2132 reference TEs that were polymorphic for their presence or absence in our study cohort. The presence or absence of the TE element could change the expression of the gene or gene clusters from zero to tens of thousands of copies of RNA. The main finding is that many TEs possess very strong regulatory effects, and they have the potential to modulate large genetic networks with hundreds of target genes over the genome. We illustrate the plethora of regulatory mechanisms using examples of their action at the HLA gene cluster and data showing different TEs' convergence to modulate WFS1 gene expression. In conclusion, the presence or absence of polymorphisms of TEs has an eminent genome-wide regulatory function with large effect size at the level of the whole transcriptome. The role of TEs in explaining, in part, the missing heritability for complex traits is convincing and should be considered.


Assuntos
Locos de Características Quantitativas/genética , Retroelementos/genética , Transcriptoma/genética , Elementos Alu/genética , Genoma Humano , Humanos , Repetições Minissatélites/genética , Doença de Parkinson/genética , Elementos Nucleotídeos Curtos e Dispersos/genética
16.
Nano Lett ; 21(14): 5967-5976, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34264082

RESUMO

Sonogenetics is a promising strategy allowing the noninvasive and selective activation of targeted neurons in deep brain regions; nevertheless, its therapeutic outcome for neurodegeneration diseases that need long-term treatment remains to be verified. We previously enhanced the ultrasound (US) sensitivity of targeted cells by genetic modification with an engineered auditory-sensing protein, mPrestin (N7T, N308S). In this study, we expressed mPrestin in the dopaminergic neurons of the substantia nigra in Parkinson's disease (PD) mice and used 0.5 MHz US for repeated and localized brain stimulation. The mPrestin expression in dopaminergic neurons persisted for at least 56 days after a single shot of adeno-associated virus, suggesting that the period of expression was long enough for US treatment in mice. Compared to untreated mice, US stimulation ameliorated the dopaminergic neurodegeneration 10-fold and mitigated the PD symptoms of the mice 4-fold, suggesting that this sonogenetic strategy has the clinical potential to treat neurodegenerative diseases.


Assuntos
Doença de Parkinson , Animais , Modelos Animais de Doenças , Dopamina , Neurônios Dopaminérgicos , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/genética , Doença de Parkinson/terapia , Substância Negra
17.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281186

RESUMO

Parkinson's disease (PD) is the most common neurodegenerative motor disorder characterized by selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain, depletion of dopamine (DA), and impaired nigrostriatal pathway. The pathological hallmark of PD includes the aggregation and accumulation α-synuclein (α-SYN). Although the precise mechanisms underlying the pathogenesis of PD are still unknown, the activation of toll-like receptors (TLRs), mainly TLR4 and subsequent neuroinflammatory immune response, seem to play a significant role. Mounting evidence suggests that viral infection can concur with the precipitation of PD or parkinsonism. The recently identified coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of ongoing pandemic coronavirus disease 2019 (COVID-19), responsible for 160 million cases that led to the death of more than three million individuals worldwide. Studies have reported that many patients with COVID-19 display several neurological manifestations, including acute cerebrovascular diseases, conscious disturbance, and typical motor and non-motor symptoms accompanying PD. In this review, the neurotropic potential of SARS-CoV-2 and its possible involvement in the pathogenesis of PD are discussed. Specifically, the involvement of the TLR4 signaling pathway in mediating the virus entry, as well as the massive immune and inflammatory response in COVID-19 patients is explored. The binding of SARS-CoV-2 spike (S) protein to TLR4 and the possible interaction between SARS-CoV-2 and α-SYN as contributing factors to neuronal death are also considered.


Assuntos
COVID-19/fisiopatologia , Doença de Parkinson/metabolismo , Doença de Parkinson/virologia , SARS-CoV-2/metabolismo , Receptor 4 Toll-Like/metabolismo , COVID-19/metabolismo , Humanos , Doença de Parkinson/genética , SARS-CoV-2/genética , Transdução de Sinais , Glicoproteína da Espícula de Coronavírus/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/fisiologia
18.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299248

RESUMO

Parkinson's disease (PD) is a complex and progressive neurodegenerative disorder with a prevalence of approximately 0.5-1% among those aged 65-70 years. Although most of its clinical manifestations are due to a loss of dopaminergic neurons, the PD etiology is largely unknown. PD is caused by a combination of genetic and environmental factors, and the exact interplay between genes and the environment is still debated. Several biological processes have been implicated in PD, including mitochondrial or lysosomal dysfunctions, alteration in protein clearance, and neuroinflammation, but a common molecular mechanism connecting the different cellular alterations remains incompletely understood. Accumulating evidence underlines a significant role of lipids in the pathological pathways leading to PD. Beside the well-described lipid alteration in idiopathic PD, this review summarizes the several lipid alterations observed in experimental models expressing PD-related genes and suggests a possible scenario in relationship to the molecular mechanisms of neuronal toxicity. PD could be considered a lipid-induced proteinopathy, where alteration in lipid composition or metabolism could induce protein alteration-for instance, alpha-synuclein accumulation-and finally neuronal death.


Assuntos
Metabolismo dos Lipídeos/genética , Lipídeos/fisiologia , Doença de Parkinson/genética , Neurônios Dopaminérgicos/metabolismo , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Fosfolipases A2 do Grupo VI/genética , Fosfolipases A2 do Grupo VI/metabolismo , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Lisossomos/metabolismo , Mitocôndrias/metabolismo , Degeneração Neural/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
19.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281267

RESUMO

BACKGROUND: Parkinson's disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson's disease. METHODS: We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson's disease treatment, along with a manual search, and finally included a total of 116 publications in the review. RESULTS: We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings. CONCLUSIONS: This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient.


Assuntos
Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/metabolismo , Antiparkinsonianos/farmacologia , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/farmacologia , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Genótipo , Humanos , Levodopa/efeitos adversos , Levodopa/metabolismo , Levodopa/farmacologia , Inibidores da Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Doença de Parkinson/metabolismo , Farmacogenética/métodos , Farmacogenética/tendências , Variantes Farmacogenômicos , Pesquisa Médica Translacional
20.
Methods Mol Biol ; 2277: 299-329, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34080159

RESUMO

In light of accumulating evidence suggestive of cell type-specific vulnerabilities as a result of normal aging processes that adversely affect the brain, as well as age-related neurodegenerative disorders such as Parkinson's disease (PD), the current chapter highlights how we study mitochondrial DNA (mtDNA) changes at a single-cell level. In particular, we comment on increasing questioning of the narrow neurocentric view of such pathologies, where microglia and astrocytes have traditionally been considered bystanders rather than players in related pathological processes. Here we review the contribution made by single-cell mtDNA alterations towards neuronal vulnerability seen in neurodegenerative disorders, focusing on PD as a prominent example. In addition, we give an overview of methodologies that support such experimental investigations. In considering the significant advances that have been made in recent times for developing mitochondria-specific therapies, investigations to account for cell type-specific mitochondrial patterns and how these are altered by disease hold promise for delivering more effective disease-modifying therapeutics.


Assuntos
Encéfalo/patologia , DNA Mitocondrial/análise , DNA Mitocondrial/genética , Doenças Neurodegenerativas/patologia , Análise de Célula Única/métodos , Envelhecimento/genética , Humanos , Doenças Neurodegenerativas/genética , Doença de Parkinson/genética , Reação em Cadeia da Polimerase/métodos
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