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1.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2368-2371, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018482

RESUMO

It has been widely accepted that Parkinson's disease (PD) is triggered and shaped by propagation of misfolded α-synuclein. Converging neurophysiological evidence suggests that leucine-rich repeat kinase 2 (LRRK2) is involved in membrane transport of PD pathogenesis. This study proposed an agent-based computational model by integrating structural connections and gene expression to investigate whether LRRK2 would affect the PD pathology propagation in central nervous system. Gene expression profiles from the Allen Human Brain Atlas (AHBA) and multimodal brain MRI images from Parkinson's Progression Markers Initiative (PPMI) and Human Connectome Project (HCP) were employed for the model construction. The model results exhibit the involvement of LRRK2 gene expression remarkably elevated model fitting (r = 0.73) compared with the traditional susceptible-infected-removed (S-I-R) model (r=0.60). Specifically, our model revealed that LRRK2 is more likely to modulate pathology secretion out of neurons, rather than spreading into neurons. The findings support the theory of LRRK2 gene expression modulating cell-to-cell propagation of misfolded proteins. As a result, the proposed model would bring new insights of understanding PD mechanism in terms of misfolded α-synuclein propagation.


Assuntos
Doença de Parkinson , alfa-Sinucleína , Encéfalo/diagnóstico por imagem , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Neurônios/metabolismo , Doença de Parkinson/genética , alfa-Sinucleína/genética
2.
Nat Commun ; 11(1): 4885, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985503

RESUMO

Parkinson's disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here we report that the molecular tweezer CLR01 decreased aggregation and toxicity in induced pluripotent stem cell-derived dopaminergic cultures treated with PD brain protein extracts. In microfluidic devices CLR01 reduced alpha-synuclein aggregation in cell somas when axonal terminals were exposed to alpha-synuclein oligomers. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated at 12 months of age when motor defects are mild exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Neurônios Dopaminérgicos/efeitos dos fármacos , Organofosfatos/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Substâncias Protetoras/administração & dosagem , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Humanos , Masculino , Camundongos , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Agregados Proteicos/efeitos dos fármacos , alfa-Sinucleína/química , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
3.
Mol Pharmacol ; 98(3): 250-266, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32817461

RESUMO

In medium-size, spiny striatal neurons of the direct pathway, dopamine D1- and adenosine A1-receptors are coexpressed and are mutually antagonistic. Recently, a mutation in the gene encoding the A1-receptor (A1R), A1R-G279S7.44, was identified in an Iranian family: two affected offspring suffered from early-onset l-DOPA-responsive Parkinson's disease. The link between the mutation and the phenotype is unclear. Here, we explored the functional consequence of the G279S substitution on the activity of the A1-receptor after heterologous expression in HEK293 cells. The mutation did not affect surface expression and ligand binding but changed the susceptibility to heat denaturation: the thermodynamic stability of A1R-G279S7.44 was enhanced by about 2 and 8 K when compared with wild-type A1-receptor and A1R-Y288A7.53 (a folding-deficient variant used as a reference), respectively. In contrast, the kinetic stability was reduced, indicating a lower energy barrier for conformational transitions in A1R-G279S7.44 (73 ± 23 kJ/mol) than in wild-type A1R (135 ± 4 kJ/mol) or in A1R-Y288A7.53 (184 ± 24 kJ/mol). Consistent with this lower energy barrier, A1R-G279S7.44 was more effective in promoting guanine nucleotide exchange than wild-type A1R. We detected similar levels of complexes formed between D1-receptors and wild-type A1R or A1R-G279S7.44 by coimmunoprecipitation and bioluminescence resonance energy transfer. However, lower concentrations of agonist were required for half-maximum inhibition of dopamine-induced cAMP accumulation in cells coexpressing D1-receptor and A1R-G279S7.44 than in those coexpressing wild-type A1R. These observations predict enhanced inhibition of dopaminergic signaling by A1R-G279S7.44 in vivo, consistent with a pathogenic role in Parkinson's disease. SIGNIFICANCE STATEMENT: Parkinson's disease is caused by a loss of dopaminergic input from the substantia nigra to the caudate nucleus and the putamen. Activation of the adenosine A1-receptor antagonizes responses elicited by dopamine D1-receptor. We show that this activity is more pronounced in a mutant version of the A1-receptor (A1R-G279S7.44), which was identified in individuals suffering from early-onset Parkinson's disease.


Assuntos
Substituição de Aminoácidos , Doença de Parkinson/genética , Receptor A1 de Adenosina/química , Receptor A1 de Adenosina/metabolismo , Células HEK293 , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Conformação Proteica , Estabilidade Proteica , Receptor A1 de Adenosina/genética , Termodinâmica
4.
Nat Commun ; 11(1): 4183, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826893

RESUMO

We describe a human single-nuclei transcriptomic atlas for the substantia nigra (SN), generated by sequencing approximately 17,000 nuclei from matched cortical and SN samples. We show that the common genetic risk for Parkinson's disease (PD) is associated with dopaminergic neuron (DaN)-specific gene expression, including mitochondrial functioning, protein folding and ubiquitination pathways. We identify a distinct cell type association between PD risk and oligodendrocyte-specific gene expression. Unlike Alzheimer's disease (AD), we find no association between PD risk and microglia or astrocytes, suggesting that neuroinflammation plays a less causal role in PD than AD. Beyond PD, we find associations between SN DaNs and GABAergic neuron gene expression and multiple neuropsychiatric disorders. Conditional analysis reveals that distinct neuropsychiatric disorders associate with distinct sets of neuron-specific genes but converge onto shared loci within oligodendrocytes and oligodendrocyte precursors. This atlas guides our aetiological understanding by associating SN cell type expression profiles with specific disease risk.


Assuntos
Expressão Gênica , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , Doença de Alzheimer/metabolismo , Astrócitos/metabolismo , Encéfalo , Neurônios Dopaminérgicos/metabolismo , Humanos , Microglia/metabolismo , Mitocôndrias/metabolismo , Doenças do Sistema Nervoso/patologia , Substância Negra/patologia , Transcriptoma
5.
Mol Cell Biol ; 40(19)2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32690545

RESUMO

Neuronal ceroid lipofuscinosis (NCL) is one of the most prevalent neurodegenerative disorders of early life, Parkinson's disease (PD) is the most common neurodegenerative disorder of midlife, while Alzheimer's disease (AD) is the most common neurodegenerative disorder of late life. While they are phenotypically distinct, recent studies suggest that they share a biological pathway, retromer-dependent endosomal trafficking. A retromer is a multimodular protein assembly critical for sorting and trafficking cargo out of the endosome. As a lysosomal storage disease, all 13 of NCL's causative genes affect endolysosomal function, and at least four have been directly linked to retromer. PD has several known causative genes, with one directly linked to retromer and others causing endolysosomal dysfunction. AD has over 25 causative genes/risk factors, with several of them linked to retromer or endosomal trafficking dysfunction. In this article, we summarize the emerging evidence on the association of genes causing NCL with retromer function and endosomal trafficking, review the recent evidence linking NCL genes to AD, and discuss how NCL, AD, and PD converge on a shared molecular pathway. We also discuss this pathway's role in microglia and neurons, cell populations which are critical to proper brain homeostasis and whose dysfunction plays a key role in neurodegeneration.


Assuntos
Doença de Alzheimer/metabolismo , Endossomos/metabolismo , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/metabolismo , Doença de Parkinson/metabolismo , Doença de Alzheimer/genética , Animais , Transporte Biológico , Humanos , Doença de Parkinson/genética , Presenilina-1/genética , Presenilina-1/metabolismo
6.
Anticancer Res ; 40(6): 3169-3190, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487612

RESUMO

BACKGROUND/AIM: During the last two decades, Parkinson's disease (PD)-associated genes have been associated with cancer; however, a shared pathogenic mechanism has yet to be discovered. Parkin, an E3 ubiquitin ligase that is involved in early-onset Parkinson's disease, has also been reported to exert tumor suppressor activity. However, the details about the role of Parkin in cancer remain unknown. The present study aimed at identifying differentially regulated nuclear proteins and nuclear phosphoproteins whose levels were affected by Parkin expression. MATERIALS AND METHODS: SHS-SY5Y cells expressing either wild-type Parkin or its mutant under tetracycline control were used in this study; cells not expressing Parkin served as control. Nuclear proteins were enriched from Parkin-expressing and control cells to perform a comparative proteomics study using two-dimensional gel electrophoresis (2D) coupled to matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF/TOF) mass spectrometry analysis. Changes in phosphoproteome and nuclear phosphoproteome were also studied by staining the 2D gels with ProQ diamond phosphoprotein stain. The identified proteins were subjected to bioinformatics analysis to elucidate the reactomes and relevant pathways. RESULTS: Six nuclear proteins, namely NCL, DDIT3, PARP1, HMGB1, TCTP and TPI were shown to be differentially regulated in cells expressing Parkin protein. Regulations in phosphorylation levels of ENPL, PRDX4, ECHM, ALDOA SET, DHSA, RCC1 and DULRD were also detected. Bioinformatics analysis of differentially regulated proteins highlighted the involvement of Parkin in DNA repair. CONCLUSION: Several nuclear protein candidates whose expression or phosphorylation levels were altered in cells expressing Parkin. Bioinformatics analysis of these proteins indicated that the nuclear form of Parkin may play a significant role in DNA repair and contribute to prevention of tumorogenesis via maintaining DNA integrity.


Assuntos
Doença de Parkinson/genética , Proteoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Linhagem Celular Tumoral , Humanos , Doença de Parkinson/patologia
7.
Fortschr Neurol Psychiatr ; 88(9): 558-566, 2020 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-32485745

RESUMO

The diverse and highly individual presentations of Parkinson's disease (PD) as a complex combination of motor and non-motor symptoms are being increasingly well characterised not least through large patient cohorts applying deep phenotyping. However, in terms of treatment of PD, the approach is uniform and purely symptomatic. Better stratification strategies with better precision medicine approaches offer opportunities to improve symptomatic treatment, define first causative therapies and provide more patient-centred care. Insight from targeted therapies for monogenic forms of PD aiming at neuroprotection may pave the way for new mechanism-based interventions also for the more common idiopathic PD. Improved stratification of patients may support symptomatic treatments by predicting treatment efficacy and long-term benefit of current pharmacological or neuromodulatory therapies, e.g. in the context of emerging pharmacogenomic knowledge. Based on asymptomatic carriers with monogenic PD or patients with REM sleep behaviour disorder (RBD), first options for applying preventive treatments emerge. The implications of these treatment strategies in relation to disease progression, and the prospects of their implementation in clinical practice need to be addressed.


Assuntos
Doença de Parkinson/genética , Doença de Parkinson/terapia , Medicina de Precisão , Progressão da Doença , Humanos , Transtorno do Comportamento do Sono REM , Resultado do Tratamento
8.
Fortschr Neurol Psychiatr ; 88(9): 601-608, 2020 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-32594506

RESUMO

More than 20 years have passed since the first description of a monogenic cause of Parkinson's disease. Despite the tremendous advances of genetic testing these techniques are rarely used in Parkinson's disease. However, genetic tests in patients with Parkinson's syndrome will play an important role in the future. This is not only to ensure the diagnosis of Parkinson's patients with a young onset and / or a positive family history, but also in the context of personalised medicine with new therapeutic options. In the following we would like to give an overview of the basics of genetic testing, the legal requirements, the procedure for genetic testing and an outlook into the future for hereditary Parkinson's diseases.


Assuntos
Testes Genéticos , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Humanos
9.
Neurology ; 95(6): e685-e696, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32540937

RESUMO

OBJECTIVE: To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and ß-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies. METHODS: A total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1-2 years). RESULTS: ß-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual ß-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean ß-glucocerebrosidase activity by 0.85 µmol/L/h (95% confidence interval, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in ß-glucocerebrosidase activity during a median 2 years of follow-up (p = 0.02). CONCLUSIONS: Residual activity of the ß-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. ß-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.


Assuntos
Glucosilceramidase/genética , Mutação , Doença de Parkinson/genética , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/etiologia , Estudos Transversais , Feminino , Seguimentos , Estudos de Associação Genética , Glucosilceramidase/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Doença de Parkinson/enzimologia , Doença de Parkinson/fisiopatologia , Doença de Parkinson/psicologia , Locos de Características Quantitativas , Índice de Gravidade de Doença
10.
PLoS One ; 15(6): e0234519, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530970

RESUMO

Axonal damage leads to the release of neurofilament light chain (NFL), which enters the CSF or blood. In this work, an assay kit for plasma NFL utilizing immunomagnetic reduction (IMR) was developed. Antibodies against NFL were immobilized on magnetic nanoparticles to develop an IMR NFL kit. The preclinical properties, such as the standard curve, limit of detection (LoD), and dynamic range, were characterized. Thirty-one normal controls (NC), fifty-two patients with Parkinson's disease (PD) or PD dementia (PDD) and thirty-one patients with Alzheimer's disease (AD) were enrolled in the study evaluating the plasma NFL assay using an IMR kit. T-tests and receiver operating characteristic (ROC) curve analysis were performed to investigate the capability for discrimination among the clinical groups according to plasma NFL levels. The LoD of the NFL assay using the IMR kit was found to be 0.18 fg/ml. The dynamic range of the NFL assay reached 1000 pg/ml. The NC group showed a plasma NFL level of 7.70 ± 4.00 pg/ml, which is significantly lower than that of the PD/PDD (15.85 ± 7.82 pg/ml, p < 0.001) and AD (19.24 ± 8.99 pg/ml, p < 0.001) groups. A significant difference in plasma NFL levels was determined between the PD and AD groups (p < 0.01). Through ROC curve analysis, the cut-off value of the plasma NFL concentration for differentiating NCs from dementia patients (AD and PD/PDD) was found to be 12.71 pg/ml, with a clinical sensitivity and specificity of 73.5% and 90.3%, respectively. The AUC was 0.868. Furthermore, the cut-off value of the plasma NFL concentration for discriminating AD from PD/PDD was found to be 18.02 pg/ml, with a clinical sensitivity and specificity of 61.3% and 65.4%, respectively. The AUC was 0.630. An ultrasensitive assay for measuring plasma NFL utilizing IMR technology was developed. Clear differences in plasma NFL concentrations were observed among NCs and PD and AD patients. These results imply that the determination of plasma NFL is promising not only for screening dementia but also for differential diagnosis.


Assuntos
Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Proteínas de Neurofilamentos/sangue , Proteínas tau/sangue , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Axônios/metabolismo , Axônios/patologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Feminino , Humanos , Separação Imunomagnética , Filamentos Intermediários/genética , Filamentos Intermediários/patologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/sangue , Doença de Parkinson/genética , Doença de Parkinson/patologia
11.
Neurol Neurochir Pol ; 54(3): 220-231, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32557526

RESUMO

INTRODUCTION: Vector-based intracerebral gene therapies are being used to treat specific neurodegenerative conditions such as Parkinson's Disease (PD). This review presents a basis for central nervous system (CNS) gene therapy treatments of neurodegenerative diseases such as PD, as well as the need for novel skill sets and health delivery strategies within the clinical neurosciences (neurology and neurosurgery) to meet future demand for such therapies. STATE OF THE ART: Preclinical vector-based gene therapy approaches have been translated into clinical trials for PD and other neurodegenerative conditions. Unfortunately, such trials, and parallel efforts using other therapeutics, have yet to provide a breakthrough. Image-guided convection enhanced delivery (CED) optimises the parenchymal distribution of gene therapies applied within the CNS, and may ultimately provide such a breakthrough. CLINICAL IMPLICATIONS: Currently, image-guided CED and gene therapy are not part of training programmes for most neurosurgeons and neurologists. As a result, few medical centres and hospitals have sufficiently experienced teams to participate in gene transfer clinical trials for PD or other neurological conditions. If CNS gene therapies prove to be efficacious for PD and/or other conditions, the demand for such treatments will overwhelm the available number of experienced clinical neuroscience teams and treatment centres. FUTURE DIRECTIONS: Expanded indications and demand for CNS gene therapies will require a worldwide educational effort to supplement the training of clinical neuroscience practitioners. Initially, a limited number of Centres of Excellence will need to establish relevant educational training requirements and best practice for such therapeutic approaches. Advanced technologies, including robotics and artificial intelligence, are especially germane in this regard, and will expand the treatment team's capabilities while assisting in the safe and timely care of those afflicted.


Assuntos
Doença de Parkinson , Inteligência Artificial , Sistema Nervoso Central , Terapia Genética , Humanos , Doença de Parkinson/genética , Doença de Parkinson/terapia
12.
PLoS Genet ; 16(6): e1008868, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32579581

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder featuring progressive loss of midbrain dopaminergic (DA) neurons that leads to motor symptoms. The etiology and pathogenesis of PD are not clear. We found that expression of COUP-TFII, an orphan nuclear receptor, in DA neurons is upregulated in PD patients through the analysis of public datasets. We show here that through epigenetic regulation, COUP-TFII contributes to oxidative stress, suggesting that COUP-TFII may play a role in PD pathogenesis. Elevated COUP-TFII expression specifically in DA neurons evokes DA neuronal loss in mice and accelerates the progression of phenotypes in a PD mouse model, MitoPark. Compared to control mice, those with elevated COUP-TFII expression displayed reduced cristae in mitochondria and enhanced cellular electron-dense vacuoles in the substantia nigra pars compacta. Mechanistically, we found that overexpression of COUP-TFII disturbs mitochondrial pathways, resulting in mitochondrial dysfunction. In particular, there is repressed expression of genes encoding cytosolic aldehyde dehydrogenases, which could enhance oxidative stress and interfere with mitochondrial function via 3,4-dihydroxyphenylacetaldehyde (DOPAL) buildup in DA neurons. Importantly, under-expression of COUP-TFII in DA neurons slowed the deterioration in motor functions of MitoPark mice. Taken together, our results suggest that COUP-TFII may be an important contributor to PD development and a potential therapeutic target.


Assuntos
Fator II de Transcrição COUP/metabolismo , Neurônios Dopaminérgicos/patologia , Mitocôndrias/patologia , Doença de Parkinson/genética , Ácido 3,4-Di-Hidroxifenilacético/análogos & derivados , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Aldeído Desidrogenase , Animais , Encéfalo/citologia , Encéfalo/patologia , Linhagem Celular , Linhagem Celular Tumoral , Estudos de Coortes , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Progressão da Doença , Neurônios Dopaminérgicos/citologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Estresse Oxidativo/genética , Doença de Parkinson/patologia , Cultura Primária de Células , RNA-Seq , Ratos , Regulação para Cima
13.
Orv Hetil ; 161(20): 821-828, 2020 05 01.
Artigo em Húngaro | MEDLINE | ID: mdl-32364361

RESUMO

The protein product of the nuclear-encoded POLG gene plays a key role in the maintenance of mitochondrial DNA replication, and its failure causes multi-system diseases with varying severity. The clinical spectrum is extremely wide, and the most common symptoms include ptosis, myoclonus, epilepsy, myopathy, sensory ataxia, parkinsonism, cognitive decline and infertility. Now, it is known that mitochondrial dysfunction in Parkinson's disease plays a key role in the loss of dopaminergic neurons in the substantia nigra. Therefore, changes in the POLG gene may influence the development of various hereditary neurodegenerative diseases, including monogenic parkinsonism. However, only limited information is available on the relationship between Parkinson's disease and POLG gene and until now, there are no available data about the Hungarian population. In our study, we performed a next-generation sequencing study of 67 Hungarian patients with parkinsonism and analyzed the potentially damaging alterations in the POLG gene. 3 patients have been identified with a potential pathogen variant. In this study, we would like to call attention to the fact that during the differential diagnosis of parkinsonism, the possible involvement of POLG gene should be kept in mind. Especially in the presence of additional symptoms, such as ophthalmoparesis, non-vascular white matter lesions, psychiatric comorbidity, and relatively early age of onset, the POLG gene should be taken into consideration. Based on previous data from the literature and our own experience, we have summarized a possible diagnostic approach for POLG-associated parkinsonism. Orv Hetil. 2020; 161(20): 821-828.


Assuntos
Polimerase do DNA Mitocondrial/genética , Predisposição Genética para Doença , Doença de Parkinson/genética , Comorbidade , DNA Mitocondrial/metabolismo , Humanos , Hungria , Transtornos Mentais/genética , Mutação , Oftalmoplegia/genética , Doença de Parkinson/diagnóstico , Transtornos Parkinsonianos/genética
14.
Nat Med ; 26(6): 869-877, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32461697

RESUMO

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5-8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.


Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Mutação com Perda de Função/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Bancos de Espécimes Biológicos , Linhagem Celular , Células-Tronco Embrionárias/metabolismo , Feminino , Mutação com Ganho de Função/genética , Heterozigoto , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Longevidade/genética , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Fenótipo
15.
Proc Natl Acad Sci U S A ; 117(22): 12428-12434, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32424101

RESUMO

Numerous genes whose mutations cause, or increase the risk of, Parkinson's disease (PD) have been identified. An inactivating mutation (R258Q) in the Sac inositol phosphatase domain of synaptojanin 1 (SJ1/PARK20), a phosphoinositide phosphatase implicated in synaptic vesicle recycling, results in PD. The gene encoding Sac2/INPP5F, another Sac domain-containing protein, is located within a PD risk locus identified by genome-wide association studies. Knock-In mice carrying the SJ1 patient mutation (SJ1RQKI) exhibit PD features, while Sac2 knockout mice (Sac2KO) do not have obvious neurologic defects. We report a "synthetic" effect of the SJ1 mutation and the KO of Sac2 in mice. Most mice with both mutations died perinatally. The occasional survivors had stunted growth, died within 3 wk, and showed abnormalities of striatal dopaminergic nerve terminals at an earlier stage than SJ1RQKI mice. The abnormal accumulation of endocytic factors observed at synapses of cultured SJ1RQKI neurons was more severe in double-mutant neurons. Our results suggest that SJ1 and Sac2 have partially overlapping functions and are consistent with a potential role of Sac2 as a PD risk gene.


Assuntos
Inositol Polifosfato 5-Fosfatases/genética , Doença de Parkinson/enzimologia , Animais , Dopamina/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Inositol Polifosfato 5-Fosfatases/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Terminações Nervosas/metabolismo , Doença de Parkinson/genética , Fenótipo , Sinapses/metabolismo
16.
DNA Cell Biol ; 39(8): 1421-1430, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32397749

RESUMO

Mitochondria are the only organelles that contain their own genetic material (mtDNA). Mitochondria are involved in several key physiological functions, including ATP production, Ca2+ homeostasis, and metabolism of neurotransmitters. Since these organelles perform crucial processes to maintain neuronal homeostasis, mitochondrial dysfunctions can lead to various neurodegenerative diseases. Several mitochondrial proteins involved in ATP production are encoded by mtDNA. Thus, any mtDNA alteration can ultimately lead to mitochondrial dysfunction and cell death. Accumulation of mutations, deletions, and rearrangements in mtDNA has been observed in animal models and patients suffering from Parkinson's disease (PD). Also, specific inherited variations associated with mtDNA genetic groups (known as mtDNA haplogroups) are associated with lower or higher risk of developing PD. Consequently, mtDNA alterations should now be considered important hallmarks of this neurodegenerative disease. This review provides an update about the role of mtDNA alterations in the physiopathology of PD.


Assuntos
DNA Mitocondrial/genética , Mitocôndrias/genética , Neurônios/metabolismo , Doença de Parkinson/genética , Animais , Dano ao DNA/genética , Humanos , Mitocôndrias/patologia , Modelos Animais , Neurônios/patologia , Doença de Parkinson/patologia
17.
Gene ; 753: 144808, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32470505

RESUMO

OBJECTIVE: C-reactive protein (CRP) is increased in Parkinson's disease (PD). The CRP +1444C/T (rs1130864) polymorphism is located in the 3' untranslated region (3'-UTR) and is associated with serum CRP concentrations. We explored the relationship between the CRP +1444C/T polymorphism and susceptibility to PD. METHODS: A total of 1000 subjects from a Chinese population were recruited into this case-control study, including 500 PD patients and 500 healthy controls. The genotype of the CRP +1444C/T polymorphism was tested by Sanger sequencing, and the Hardy-Weinberg equilibrium (HWE) was assessed in the groups. The odds ratios and 95% confidence intervals were calculated to evaluate the strength of any correlations in allelic, dominant, recessive, and additive genetic models. RESULTS: The genotypic distribution of the CRP +1444C/T polymorphism was consistent with HWE in controls, and markedly different with cases. The CRP +1444C/T polymorphism was associated with increased PD risk in allelic and dominant models in the overall and male population, but not the female subgroup. CONCLUSION: The presence of a CRP +1444C/T polymorphism may be associated with an increased risk of PD in our Chinese population. Given the missing support for a role of this SNP in PD in the pre-existing GWAS, the SNP may not be genuinely associated with PD despite some positive candidate gene studies.


Assuntos
Proteína C-Reativa/genética , Doença de Parkinson/genética , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Suscetibilidade a Doenças , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
18.
Nat Commun ; 11(1): 2643, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32457390

RESUMO

Amyloid aggregation of α-synuclein (α-syn) is closely associated with Parkinson's disease (PD) and other synucleinopathies. Several single amino-acid mutations (e.g. E46K) of α-syn have been identified causative to the early onset of familial PD. Here, we report the cryo-EM structure of an α-syn fibril formed by N-terminally acetylated E46K mutant α-syn (Ac-E46K). The fibril structure represents a distinct fold of α-syn, which demonstrates that the E46K mutation breaks the electrostatic interactions in the wild type (WT) α-syn fibril and thus triggers the rearrangement of the overall structure. Furthermore, we show that the Ac-E46K fibril is less resistant to harsh conditions and protease cleavage, and more prone to be fragmented with an enhanced seeding capability than that of the WT fibril. Our work provides a structural view to the severe pathology of the PD familial mutation E46K of α-syn and highlights the importance of electrostatic interactions in defining the fibril polymorphs.


Assuntos
Proteínas Mutantes/química , Proteínas Mutantes/genética , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , alfa-Sinucleína/química , alfa-Sinucleína/genética , Acetilação , Sequência de Aminoácidos , Substituição de Aminoácidos , Amiloide/química , Amiloide/genética , Amiloide/ultraestrutura , Microscopia Crioeletrônica , Humanos , Microscopia de Força Atômica , Modelos Moleculares , Proteínas Mutantes/ultraestrutura , Mutação de Sentido Incorreto , Conformação Proteica , Estabilidade Proteica , Eletricidade Estática , alfa-Sinucleína/ultraestrutura
20.
J Integr Neurosci ; 19(1): 51-64, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32259886

RESUMO

TGM6 encodes transglutaminase 6, which catalyzes the covalent crosslinking of proteins through transamination reactions. Variants in TGM6 have been identified as the cause of spinocerebellar ataxia type 35. However, we found 12 TGM6 variants of low frequency among 308 patients with Parkinson's disease using next-generation sequencing technologies and multiple ligation-dependent probe amplification, including two variants TGM6 p.R111C and p.L517W, which have been reported to affect functions of transglutaminase 6 in spinocerebellar ataxia type 35 cases. The characteristics of these TGM6 carriers were summarized. To clarify the role of TGM6 variants in Parkinson's disease, we constructed the plasmids of wild-type TGM6 and TGM6 p.R111C, p.P359L, p.L517W to transfect A53T-SH-SY5Y cells and conducted transglutaminase assay, western blots, immunofluorescence, and cell viability assay. Results revealed that the distribution and expression levels of transglutaminase 6 were not affected by TGM6 variants. However, the variants showed lower transglutaminase activity than wild-type transglutaminase 6. The overexpression of wild-type TGM6 was proved to relieve the cell damage, down-regulate the level of α-synuclein and enhance autophagy. These effects were weakened in cells transfected with mutant TGM6 plasmids. Our results suggested that there may be some relationship between TGM6 and Parkinson's disease. TGM6 carriers in Parkinson's disease patients presented with typical parkinsonism but progressed slower. The high expression level of wild-type transglutaminase 6 may protect cells by decreasing α-synuclein and enhancing autophagy.


Assuntos
Doença de Parkinson/genética , Transglutaminases/genética , Adolescente , Adulto , Autofagia , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Doença de Parkinson/metabolismo , Linhagem , alfa-Sinucleína/metabolismo
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