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1.
Nat Rev Neurosci ; 25(6): 393-413, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38600347

RESUMO

Parkinson disease (PD) is a neurodegenerative disorder marked by the preferential dysfunction and death of dopaminergic neurons in the substantia nigra. The onset and progression of PD is influenced by a diversity of genetic variants, many of which lack functional characterization. To identify the most high-yield targets for therapeutic intervention, it is important to consider the core cellular compartments and functional pathways upon which the varied forms of pathogenic dysfunction may converge. Here, we review several key PD-linked proteins and pathways, focusing on the mechanisms of their potential convergence in disease pathogenesis. These dysfunctions primarily localize to a subset of subcellular compartments, including mitochondria, lysosomes and synapses. We discuss how these pathogenic mechanisms that originate in different cellular compartments may coordinately lead to cellular dysfunction and neurodegeneration in PD.


Assuntos
Doença de Parkinson , Doença de Parkinson/genética , Doença de Parkinson/patologia , Doença de Parkinson/metabolismo , Humanos , Animais , Mitocôndrias/genética , Mitocôndrias/metabolismo , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/metabolismo , Lisossomos/metabolismo , Lisossomos/genética , Sinapses/patologia , Sinapses/genética , Sinapses/metabolismo
2.
Cell ; 146(1): 37-52, 2011 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-21700325

RESUMO

Parkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of α-synuclein (α-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified α-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that α-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of α-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies.


Assuntos
Doença de Gaucher/metabolismo , Glucosilceramidase/metabolismo , alfa-Sinucleína/metabolismo , Animais , Encéfalo/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Retroalimentação Fisiológica , Doença de Gaucher/patologia , Glucosilceramidas/metabolismo , Humanos , Lisossomos/metabolismo , Camundongos , Neurônios/metabolismo
3.
Proc Natl Acad Sci U S A ; 120(44): e2313010120, 2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37878717

RESUMO

Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk and bidirectional regulation of their dynamics in health and disease. However, mitochondria-lysosome contact sites and their misregulation have not been investigated in peripheral sensory neurons. Charcot-Marie-Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting peripheral sensory neurons caused by mutations in the GTPase Rab7. Using live super-resolution and confocal time-lapse microscopy, we showed that mitochondria-lysosome contact sites dynamically form in the soma and axons of peripheral sensory neurons. Interestingly, Charcot-Marie-Tooth type 2B mutant Rab7 led to prolonged mitochondria-lysosome contact site tethering preferentially in the axons of peripheral sensory neurons, due to impaired Rab7 GTP hydrolysis-mediated contact site untethering. We further generated a Charcot-Marie-Tooth type 2B mutant Rab7 knock-in mouse model which exhibited prolonged axonal mitochondria-lysosome contact site tethering and defective downstream axonal mitochondrial dynamics due to impaired Rab7 GTP hydrolysis as well as fragmented mitochondria in the axon of the sciatic nerve. Importantly, mutant Rab7 mice further demonstrated preferential sensory behavioral abnormalities and neuropathy, highlighting an important role for mutant Rab7 in driving degeneration of peripheral sensory neurons. Together, this study identifies an important role for mitochondria-lysosome contact sites in the pathogenesis of peripheral neuropathy.


Assuntos
Doença de Charcot-Marie-Tooth , Proteínas rab de Ligação ao GTP , Animais , Camundongos , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo , proteínas de unión al GTP Rab7 , Doença de Charcot-Marie-Tooth/metabolismo , Células Receptoras Sensoriais/metabolismo , Mutação , Mitocôndrias/metabolismo , Lisossomos/metabolismo , Guanosina Trifosfato/metabolismo
4.
Proc Natl Acad Sci U S A ; 120(17): e2217396120, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-37068235

RESUMO

Octopamine is a well-established invertebrate neurotransmitter involved in fight or flight responses. In mammals, its function was replaced by epinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of α-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Physiological levels of neuron-derived octopamine act on astrocytes via a trace amine-associated receptor 1-Orai1-Ca2+-calcineurin-mediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the monocarboxylase transporter 2-calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by α-synuclein halt lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a unique function of octopamine as a modulator of astrocyte metabolism and subsequent neuroprotection with implications to α-synucleinopathies.


Assuntos
Octopamina , alfa-Sinucleína , Animais , alfa-Sinucleína/metabolismo , Astrócitos/metabolismo , Calcineurina/metabolismo , Lactatos/metabolismo , Mamíferos/metabolismo , Neuroproteção , Neurotransmissores/metabolismo , Octopamina/metabolismo
5.
Ann Neurol ; 95(6): 1162-1172, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38563317

RESUMO

OBJECTIVE: To characterize DNA methylation (DNAm) differences between sporadic Parkinson's disease (PD) and healthy control (HC) individuals enrolled in the Parkinson's Progression Markers Initiative (PPMI). METHODS: Using whole blood, we characterized longitudinal differences in DNAm between sporadic PD patients (n = 196) and HCs (n = 86) enrolled in PPMI. RNA sequencing (RNAseq) was used to conduct gene expression analyses for genes mapped to differentially methylated cytosine-guanine sites (CpGs). RESULTS: At the time of patient enrollment, 5,178 CpGs were differentially methylated (2,683 hypermethylated and 2,495 hypomethylated) in PD compared to HC. Of these, 579 CpGs underwent significant methylation changes over 3 years. Several differentially methylated CpGs were found near the cytochrome P450 family 2 subfamily E member 1 (CYP2E1) gene. Additionally, multiple hypermethylated CpGs were associated with the N-myc downregulated gene family member 4 (NDRG4) gene. RNA-Seq analyses showed 75 differentially expressed genes in PD patients compared to controls. An integrative analysis of both differentially methylated sites and differentially expressed genes revealed 20 genes that exhibited hypomethylation concomitant with overexpression. Additionally, 1 gene, cathepsin H (CTSH), displayed hypermethylation that was associated with its decreased expression. INTERPRETATION: We provide initial evidence of alterations in DNAm in blood of PD patients that may serve as potential epigenetic biomarker of disease. To evaluate the significance of these changes throughout the progression of PD, additional profiling at longer intervals and during the prodromal stages of disease will be necessary. ANN NEUROL 2024;95:1162-1172.


Assuntos
Biomarcadores , Metilação de DNA , Epigênese Genética , Doença de Parkinson , Humanos , Doença de Parkinson/genética , Doença de Parkinson/sangue , Masculino , Feminino , Metilação de DNA/genética , Idoso , Pessoa de Meia-Idade , Biomarcadores/sangue , Epigênese Genética/genética , Epigenoma/genética , Ilhas de CpG/genética
6.
Hum Mol Genet ; 31(14): 2424-2437, 2022 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-35181782

RESUMO

Variants in multiple lysosomal enzymes increase Parkinson's disease (PD) risk, including the genes encoding glucocerebrosidase (GCase), acid sphingomyelinase (ASMase) and galactosylceramidase. Each of these enzymes generates ceramide by hydrolysis of sphingolipids in lysosomes, but the role of this common pathway in PD pathogenesis has not yet been explored. Variations in GBA1, the gene encoding GCase, are the most common genetic risk factor for PD. The lysosomal enzyme cathepsin B has recently been implicated as an important genetic modifier of disease penetrance in individuals harboring GBA1 variants, suggesting a mechanistic link between these enzymes. Here, we found that ceramide activates cathepsin B, and identified a novel role for cathepsin B in mediating prosaposin cleavage to form saposin C, the lysosomal coactivator of GCase. Interestingly, this pathway was disrupted in Parkin-linked PD models, and upon treatment with inhibitor of ASMase which resulted in decreased ceramide production. Conversely, increasing ceramide production by inhibiting acid ceramidase activity was sufficient to upregulate cathepsin B- and saposin C-mediated activation of GCase. These results highlight a mechanistic link between ceramide and cathepsin B in regulating GCase activity and suggest that targeting lysosomal ceramide or cathepsin B represents an important therapeutic strategy for activating GCase in PD and related disorders.


Assuntos
Glucosilceramidase , Doença de Parkinson , Catepsina B/genética , Catepsina B/metabolismo , Ceramidas/metabolismo , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Humanos , Lisossomos/metabolismo , Doença de Parkinson/metabolismo , Saposinas/genética , Saposinas/metabolismo , alfa-Sinucleína/metabolismo
7.
Mov Disord ; 39(8): 1282-1288, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38858837

RESUMO

Parkinson's disease (PD) is characterized by preferential degeneration of midbrain dopaminergic neurons that contributes to its typical clinical manifestation. Mutations in the parkin gene (PARK2) represent a relatively common genetic cause of early onset PD. Parkin has been implicated in PINK1-dependent mitochondrial quantity control by targeting dysfunctional mitochondria to lysosomes via mitophagy. Recent evidence suggests that parkin can be activated in PINK1-independent manner to regulate synaptic function in human dopaminergic neurons. Neuronal activity triggers CaMKII-mediated activation of parkin and its recruitment to synaptic vesicles where parkin promotes binding of synaptojanin-1 to endophilin A1 and facilitates vesicle endocytosis. In PD patient neurons, disruption of this pathway on loss of parkin leads to defective recycling of synaptic vesicles and accumulation of toxic oxidized dopamine that at least in part explains preferential vulnerability of midbrain dopaminergic neurons. These findings suggest a convergent mechanism for PD-linked mutations in parkin, synaptojanin-1, and endophilin A1 and highlight synaptic dysfunction as an early pathogenic event in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Neurônios Dopaminérgicos , Mesencéfalo , Doença de Parkinson , Ubiquitina-Proteína Ligases , Humanos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologia , Mesencéfalo/metabolismo , Mesencéfalo/patologia , Animais , Mutação
8.
Mov Disord ; 39(7): 1231-1236, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38576116

RESUMO

BACKGROUND: FRMD5 variants were recently identified in patients with developmental delay, ataxia, and eye movement abnormalities. OBJECTIVES: We describe 2 patients presenting with childhood-onset ataxia, nystagmus, and seizures carrying pathogenic de novo FRMD5 variants. Weighted gene co-expression network analysis (WGCNA) was performed to gain insights into the function of FRMD5 in the brain. METHODS: Trio-based whole-exome sequencing was performed in both patients, and CoExp web tool was used to conduct WGCNA. RESULTS: Both patients presented with developmental delay, childhood-onset ataxia, nystagmus, and seizures. Previously unreported findings were diffuse choreoathetosis and dystonia of the hands (patient 1) and areas of abnormal magnetic resonance imaging signal in the white matter (patient 2). WGCNA showed that FRMD5 belongs to gene networks involved in neurodevelopment and oligodendrocyte function. CONCLUSIONS: We expanded the phenotype of FRMD5-related disease and shed light on its role in brain function and development. We recommend including FRMD5 in the genetic workup of childhood-onset ataxia and nystagmus. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Mutação de Sentido Incorreto , Nistagmo Patológico , Convulsões , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Idade de Início , Ataxia/genética , Ataxia/fisiopatologia , Proteínas do Citoesqueleto/genética , Sequenciamento do Exoma , Nistagmo Patológico/genética , Convulsões/genética
9.
Brain ; 146(1): 65-74, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36347471

RESUMO

Parkinson's disease is a complex neurodegenerative disorder with a strong genetic component, for which most known disease-associated variants are single nucleotide polymorphisms (SNPs) and small insertions and deletions (indels). DNA repetitive elements account for >50% of the human genome; however, little is known of their contribution to Parkinson's disease aetiology. While select short tandem repeats (STRs) within candidate genes have been studied in Parkinson's disease, their genome-wide contribution remains unknown. Here we present the first genome-wide association study of STRs in Parkinson's disease. Through a meta-analysis of 16 imputed genome-wide association study cohorts from the International Parkinson's Disease Genomic Consortium (IPDGC), totalling 39 087 individuals (16 642 cases and 22 445 controls of European ancestry), we identified 34 genome-wide significant STR loci (P < 5.34 × 10-6), with the strongest signal located in KANSL1 [chr17:44 205 351:[T]11, P = 3 × 10-39, odds ratio = 1.31 (95% confidence interval = 1.26-1.36)]. Conditional-joint analyses suggested that four significant STRs mapping nearby NDUFAF2, TRIML2, MIRNA-129-1 and NCOR1 were independent from known risk SNPs. Including STRs in heritability estimates increased the variance explained by SNPs alone. Gene expression analysis of STRs (eSTRs) in RNA sequencing data from 13 brain regions identified significant associations of STRs influencing the expression of multiple genes, including known Parkinson's disease genes. Further functional annotation of candidate STRs revealed that significant eSTRs within NUDFAF2 and ZSWIM7 overlap with regulatory features and are associated with change in the expression levels of nearby genes. Here, we show that STRs at known and novel candidate loci contribute to Parkinson's disease risk and have functional effects in disease-relevant tissues and pathways, supporting previously reported disease-associated genes and giving further evidence for their functional prioritization. These data represent a valuable resource for researchers currently dissecting Parkinson's disease risk loci.


Assuntos
MicroRNAs , Doença de Parkinson , Humanos , Doença de Parkinson/genética , Estudo de Associação Genômica Ampla , Fatores de Risco , Genoma Humano , Polimorfismo de Nucleotídeo Único/genética , Repetições de Microssatélites/genética , Predisposição Genética para Doença/genética , Proteínas de Transporte/genética
10.
Brain ; 146(7): 2730-2738, 2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-36860166

RESUMO

ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism.


Assuntos
Distonia , Distúrbios Distônicos , Humanos , Distonia/genética , Distúrbios Distônicos/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Mutação de Sentido Incorreto , Linhagem , Proteínas/genética
11.
Cell ; 137(1): 60-72, 2009 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-19345187

RESUMO

Huntington's disease (HD) is an incurable neurodegenerative disease caused by neuronal accumulation of the mutant protein huntingtin. Improving clearance of the mutant protein is expected to prevent cellular dysfunction and neurodegeneration in HD. We report here that such clearance can be achieved by posttranslational modification of the mutant Huntingtin (Htt) by acetylation at lysine residue 444 (K444). Increased acetylation at K444 facilitates trafficking of mutant Htt into autophagosomes, significantly improves clearance of the mutant protein by macroautophagy, and reverses the toxic effects of mutant huntingtin in primary striatal and cortical neurons and in a transgenic C. elegans model of HD. In contrast, mutant Htt that is rendered resistant to acetylation dramatically accumulates and leads to neurodegeneration in cultured neurons and in mouse brain. These studies identify acetylation as a mechanism for removing accumulated protein in HD, and more broadly for actively targeting proteins for degradation by autophagy.


Assuntos
Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Fagossomos/metabolismo , Acetilação , Animais , Animais Geneticamente Modificados , Células COS , Caenorhabditis elegans/metabolismo , Células Cultivadas , Chlorocebus aethiops , Técnicas de Introdução de Genes , Proteína Huntingtina , Doença de Huntington/metabolismo , Camundongos , Processamento de Proteína Pós-Traducional , Ratos
12.
Nature ; 554(7692): 382-386, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29364868

RESUMO

Both mitochondria and lysosomes are essential for maintaining cellular homeostasis, and dysfunction of both organelles has been observed in multiple diseases. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network, which drives cellular metabolism. Lysosomes similarly undergo constant dynamic regulation by the RAB7 GTPase, which cycles from an active GTP-bound state into an inactive GDP-bound state upon GTP hydrolysis. Here we have identified the formation and regulation of mitochondria-lysosome membrane contact sites using electron microscopy, structured illumination microscopy and high spatial and temporal resolution confocal live cell imaging. Mitochondria-lysosome contacts formed dynamically in healthy untreated cells and were distinct from damaged mitochondria that were targeted into lysosomes for degradation. Contact formation was promoted by active GTP-bound lysosomal RAB7, and contact untethering was mediated by recruitment of the RAB7 GTPase-activating protein TBC1D15 to mitochondria by FIS1 to drive RAB7 GTP hydrolysis and thereby release contacts. Functionally, lysosomal contacts mark sites of mitochondrial fission, allowing regulation of mitochondrial networks by lysosomes, whereas conversely, mitochondrial contacts regulate lysosomal RAB7 hydrolysis via TBC1D15. Mitochondria-lysosome contacts thus allow bidirectional regulation of mitochondrial and lysosomal dynamics, and may explain the dysfunction observed in both organelles in various human diseases.


Assuntos
Lisossomos/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Proteínas rab de Ligação ao GTP/metabolismo , Sítios de Ligação , Proteínas Ativadoras de GTPase/metabolismo , Guanosina Trifosfato/metabolismo , Células HeLa , Humanos , Hidrólise , Membranas Intracelulares/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Mitofagia , proteínas de unión al GTP Rab7
13.
Hum Mol Genet ; 30(1): 78-86, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33448283

RESUMO

Biallelic Parkin (PRKN) mutations cause autosomal recessive Parkinson's disease (PD); however, the role of monoallelic PRKN mutations as a risk factor for PD remains unclear. We investigated the role of single heterozygous PRKN mutations in three large independent case-control cohorts totalling 10 858 PD cases and 8328 controls. Overall, after exclusion of biallelic carriers, single PRKN mutations were more common in PD than controls conferring a >1.5-fold increase in the risk of PD [P-value (P) = 0.035], with meta-analysis (19 574 PD cases and 468 488 controls) confirming increased risk [Odds ratio (OR) = 1.65, P = 3.69E-07]. Carriers were shown to have significantly younger ages at the onset compared with non-carriers (NeuroX: 56.4 vs. 61.4 years; exome: 38.5 vs. 43.1 years). Stratifying by mutation type, we provide preliminary evidence for a more pathogenic risk profile for single PRKN copy number variant (CNV) carriers compared with single nucleotide variant carriers. Studies that did not assess biallelic PRKN mutations or consist of predominantly early-onset cases may be biasing these estimates, and removal of these resulted in a loss of association (OR = 1.23, P = 0.614; n = 4). Importantly, when we looked for additional CNVs in 30% of PD cases with apparent monoallellic PRKN mutations, we found that 44% had biallelic mutations, suggesting that previous estimates may be influenced by cryptic biallelic mutation status. While this study supports the association of single PRKN mutations with PD, it highlights confounding effects; therefore, caution is needed when interpreting current risk estimates. Together, we demonstrate that comprehensive assessment of biallelic mutation status is essential when elucidating PD risk associated with monoallelic PRKN mutations.


Assuntos
Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Doença de Parkinson/genética , Ubiquitina-Proteína Ligases/genética , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Doença de Parkinson/patologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
14.
Biochem Biophys Res Commun ; 644: 25-33, 2023 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-36621149

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of α-synuclein aggregates in form of Lewy bodies. Genome-wide association studies have revealed that human leukocyte antigen (HLA) class II is a PD-associated gene, although the mechanisms linking HLA class II and PD remain elusive. Here, we identified a novel function of HLA class II in the transport of intracellular α-synuclein to the outside of cells. HLA class II molecules and α-synuclein formed complexes and moved to the cell surface at various degrees among HLA-DR alleles. HLA-DR with a DRB5∗01:01 allele, a putative PD-risk allele, substantially translocated normal and conformationally abnormal α-synuclein to the cell surface and extracellular vesicles. α-Synuclein/HLA class II complexes were found in A2058 melanoma cells, which express intrinsic α-synuclein and HLA-DR with DRB5∗01:01. Our findings will expand our knowledge of unconventional HLA class II function from autoimmune diseases to neurodegenerative disorders, shedding light on the association between the GWAS-prioritized PD-risk gene HLA-DR and α-synuclein.


Assuntos
Doença de Parkinson , alfa-Sinucleína , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Estudo de Associação Genômica Ampla , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Corpos de Lewy/metabolismo , Antígenos HLA
15.
Clin Genet ; 103(1): 103-108, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36071510

RESUMO

Keppen-Lubinsky syndrome is caused by pathogenic variants in KCNJ6, which encodes the inwardly rectifying channel subfamily J6. The four confirmed cases reported to date were characterized by severe intellectual disability, global developmental delay, feeding difficulties, and dysmorphic features. All but one of the cases also had a severe form of lipodystrophy, resulting in tightly adherent facial skin and appearance of premature aging. Here, we describe a 36-year-old female with a de novo pathogenic variant in KCNJ6 (NM_002240.5: c.460G>T; p.(Gly154Cys)) presenting with mild intellectual disability, subtle dysmorphic features, obsessive-compulsive disorder, and an exaggerated startle response. This case indicates that KCNJ6-related disorders should be considered in patients with less pronounced dysmorphic features and milder cognitive impairment, as well as in patients with startle disorders.


Assuntos
Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G , Reflexo de Sobressalto , Humanos , Reflexo de Sobressalto/genética
16.
Proc Natl Acad Sci U S A ; 117(32): 19266-19275, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32703809

RESUMO

Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria-lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified a role for mitochondria-lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which was mediated by tethering of mitochondria-lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria-lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria-lysosome contact dynamics and defective contact-dependent mitochondrial calcium uptake. Thus, our work highlights mitochondria-lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes.


Assuntos
Cálcio/metabolismo , Lisossomos/metabolismo , Mitocôndrias/metabolismo , Mucolipidoses/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo , Transporte Biológico , Humanos , Lisossomos/genética , Mitocôndrias/genética , Dinâmica Mitocondrial , Mucolipidoses/genética , Canais de Potencial de Receptor Transitório/genética
17.
Hum Mol Genet ; 29(5): 716-726, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-31600775

RESUMO

Frontotemporal dementia (FTD) is a common neurogenerative disorder characterized by progressive degeneration in the frontal and temporal lobes. Heterozygous mutations in the gene encoding progranulin (PGRN) are a common genetic cause of FTD. Recently, PGRN has emerged as an important regulator of lysosomal function. Here, we examine the impact of PGRN mutations on the processing of full-length prosaposin to individual saposins, which are critical regulators of lysosomal sphingolipid metabolism. Using FTD-PGRN patient-derived cortical neurons differentiated from induced pluripotent stem cells, as well as post-mortem tissue from patients with FTLD-PGRN, we show that PGRN haploinsufficiency results in impaired processing of prosaposin to saposin C, a critical activator of the lysosomal enzyme glucocerebrosidase (GCase). Additionally, we found that PGRN mutant neurons had reduced lysosomal GCase activity, lipid accumulation and increased insoluble α-synuclein relative to isogenic controls. Importantly, reduced GCase activity in PGRN mutant neurons is rescued by treatment with saposin C. Together, these findings suggest that reduced GCase activity due to impaired processing of prosaposin may contribute to pathogenesis of FTD resulting from PGRN mutations.


Assuntos
Demência Frontotemporal/patologia , Glucosilceramidase/metabolismo , Mutação , Progranulinas/genética , Processamento de Proteína Pós-Traducional , Saposinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Demência Frontotemporal/enzimologia , Demência Frontotemporal/genética , Células HEK293 , Haploinsuficiência , Heterozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/patologia , Saposinas/química
18.
Ann Neurol ; 89(4): 828-833, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33443317

RESUMO

The Mediator multiprotein complex functions as a regulator of RNA polymerase II-catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828-833.


Assuntos
Cerebelo/anormalidades , Deficiências do Desenvolvimento/genética , Distonia/genética , Complexo Mediador/genética , Malformações do Sistema Nervoso/genética , Adolescente , Adulto , Sequência de Aminoácidos , Catarata/genética , Criança , Pré-Escolar , Epilepsia/genética , Variação Genética , Humanos , Lactente , Fenótipo , Sequenciamento do Exoma
19.
J Neurosci ; 40(45): 8618-8628, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33046546

RESUMO

The pathologic hallmark of Parkinson's disease is the accumulation of α-synuclein-containing Lewy bodies/neurites almost exclusively in neurons, and rarely in glial cells. However, emerging evidence suggests that glia such as astrocytes play an important role in the development of α-synuclein pathology. Using induced pluripotent stem-derived dopaminergic neurons and astrocytes from healthy subjects and patients carrying mutations in lysosomal ATP13A2, a monogenic form of synucleinopathy, we found that astrocytes rapidly internalized α-synuclein, and exhibited higher lysosomal degradation rates compared with neurons. Moreover, coculturing astrocytes and neurons led to decreased accumulation of α-synuclein in neurons and consequently diminished interneuronal transfer of α-synuclein. These protective functions of astrocytes were attenuated by ATP13A2 deficiency, suggesting that the loss of ATP13A2 function in astrocytes at least partially contributes to neuronal α-synuclein pathology. Together, our results highlight the importance of lysosomal function in astrocytes in the pathogenesis of synucleinopathies.SIGNIFICANCE STATEMENT While most neurodegenerative disorders are characterized by the accumulation of aggregated mutant proteins exclusively in neurons, the contribution of glial cells in this process remains poorly explored. Here, we demonstrate that astrocytes contribute to the removal of extracellular α-synuclein and that disruption of this pathway caused by mutations in the Parkinson's disease-linked gene ATP13A2 result in α-synuclein accumulation in human dopaminergic neurons. We found that astrocytes also protect neurons from α-synuclein propagation, whereas ATP13A2 deficiency in astrocytes compromises this protective function. These results highlight astrocyte-mediated α-synuclein clearance as a potential therapeutic target in disorders characterized by the accumulation of α-synuclein, including Parkinson's disease.


Assuntos
Astrócitos/fisiologia , Neurônios Dopaminérgicos/fisiologia , alfa-Sinucleína/metabolismo , Adulto , Técnicas de Cocultura , Neurônios Dopaminérgicos/metabolismo , Exossomos/metabolismo , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas , Lisossomos/enzimologia , Lisossomos/metabolismo , Masculino , Neuroglia/metabolismo , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/metabolismo , ATPases Translocadoras de Prótons/deficiência , ATPases Translocadoras de Prótons/genética , ATPases Translocadoras de Prótons/metabolismo , Sinucleinopatias/genética , Sinucleinopatias/metabolismo , alfa-Sinucleína/biossíntese
20.
Neurobiol Dis ; 159: 105513, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34536552

RESUMO

Autophagic dysregulation and lysosomal impairment have been implicated in the pathogenesis of Parkinson's disease, partly due to the identification of mutations in multiple genes involved in these pathways such as GBA, SNCA, ATP13a2 (also known as PARK9), TMEM175 and LRRK2. Mutations resulting in lysosomal dysfunction are proposed to contribute to Parkinson's disease by increasing α-synuclein levels, that in turn may promote aggregation of this protein. Here, we used two different genetic models-one heterozygous for a mutated form of the GBA protein (D409V), and the other heterozygous for an ATP13a2 loss-of-function mutation, to test whether these mutations exacerbate the spread of α-synuclein pathology following injection of α-synuclein preformed fibrils in the olfactory bulb of 12-week-old mice. Contrary to our hypothesis, we found that mice harboring GBA D409V+/- and ATP13a2+/- mutations did not have exacerbated behavioral impairments or histopathology (α-synuclein, LAMP2, and Iba1) when compared to their wildtype littermates. This indicates that in the young mouse brain, neither the GBA D409V mutation or ATP13a2 loss-of-function mutation accelerate the spread of α-synuclein pathology. As a consequence, we postulate that these mutations increase Parkinson's disease risk only by acting in one of the initial, upstream events in the Parkinson's disease pathogenic process. Further, the mutations, and the molecular pathways they impact, appear to play a less important role once the pathogenic process has been triggered and therefore do not specifically influence α-synuclein pathology spread.


Assuntos
Autofagia/genética , Glucosilceramidase/genética , Transtornos Parkinsonianos/genética , Agregados Proteicos , ATPases Translocadoras de Prótons/genética , Olfato/genética , alfa-Sinucleína/metabolismo , Animais , Comportamento Animal , Heterozigoto , Locomoção , Mutação com Perda de Função , Camundongos , Mutação , Bulbo Olfatório , Córtex Olfatório/patologia , Córtex Olfatório/fisiopatologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Córtex Perirrinal/patologia , Córtex Perirrinal/fisiopatologia , Sintomas Prodrômicos , Olfato/fisiologia
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