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1.
Nature ; 611(7937): 769-779, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36385529

RESUMO

APOE4 is the strongest genetic risk factor for Alzheimer's disease1-3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease4-8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2-6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.


Assuntos
Apolipoproteína E4 , Encéfalo , Colesterol , Fibras Nervosas Mielinizadas , Oligodendroglia , Animais , Humanos , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Colesterol/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Autopsia , Células-Tronco Pluripotentes Induzidas , Neurônios/metabolismo , Neurônios/patologia , Heterozigoto , Transporte Biológico , Homeostase , Análise de Célula Única , Memória , Envelhecimento/genética , Perfilação da Expressão Gênica , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia
2.
Neurobiol Dis ; 146: 105079, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32961270

RESUMO

Microtubule Associated Protein Tau (MAPT) forms proteopathic aggregates in several diseases. The G273R tau mutation, located in the first repeat region, was found by exome sequencing in a patient who presented with dementia and parkinsonism. We herein return to pathological examination which demonstrated tau immunoreactivity in neurons and glia consistent of mixed progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) features. To rationalize the pathological findings, we used molecular biophysics to characterize the mutation in more detail in vitro and in Drosophila. The G273R mutation increases the aggregation propensity of 4-repeat (4R) tau and alters the tau binding affinity towards microtubules (MTs) and F-actin. Tau aggregates in PSP and CBD are predominantly 4R tau. Our data suggest that the G273R mutation induces a shift in pool of 4R tau by lower F-actin affinity, alters the conformation of MT bound 4R tau, while increasing chaperoning of 3R tau by binding stronger to F-actin. The mutation augmented fibrillation of 4R tau initiation in vitro and in glial cells in Drosophila and showed preferential seeding of 4R tau in vitro suggestively causing a late onset 4R tauopathy reminiscent of PSP and CBD.


Assuntos
Encéfalo/patologia , Neurônios/metabolismo , Paralisia Supranuclear Progressiva/metabolismo , Tauopatias/patologia , Animais , Doenças dos Gânglios da Base/metabolismo , Encéfalo/metabolismo , Drosophila , Mutação/genética , Neuroglia/metabolismo
3.
Acta Neuropathol ; 139(4): 717-734, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31950334

RESUMO

Corticobasal degeneration typically progresses gradually over 5-7 years from onset till death. Fulminant corticobasal degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed corticobasal degeneration cases collected from 14 centres, we identified 6 RP-CBD cases (4.8%) who died of advanced disease within 3 years of onset. These RP-CBD cases had different clinical phenotypes including rapid global cognitive decline (N = 2), corticobasal syndrome (N = 2) and Richardson's syndrome (N = 2). We also studied four corticobasal degeneration cases with an average disease duration of 3 years or less, who died of another unrelated illness (Intermediate-CBD). Finally, we selected 12 age-matched corticobasal degeneration cases out of a cohort of 110, who had a typical gradually progressive course and reached advanced clinical stage (End-stage-CBD). Quantitative analysis showed high overall tau burden (p = 0.2) and severe nigral cell loss (p = 0.47) in both the RP-CBD and End-stage-CBD groups consistent with advanced pathological changes, while the Intermediate-CBD group (mean disease duration = 3 years) had milder changes than End-stage-CBD (p < 0.05). These findings indicated that RP-CBD cases had already developed advanced pathological changes as those observed in End-stage-CBD cases (mean disease duration = 6.7 years), but within a significantly shorter duration (2.5 years; p < 0.001). Subgroup analysis was performed to investigate the cellular patterns of tau aggregates in the anterior frontal cortex and caudate by comparing neuronal-to-astrocytic plaque ratios between six RP-CBD cases, four Intermediate-CBD and 12 age-matched End-stage-CBD. Neuronal-to-astrocytic plaque ratios of Intermediate-CBD and End-stage-CBD, but not RP-CBD, positively correlated with disease duration in both the anterior frontal cortex and caudate (p = 0.02). In contrast to the predominance of astrocytic plaques we previously reported in preclinical asymptomatic corticobasal degeneration cases, neuronal tau aggregates predominated in RP-CBD exceeding those in Intermediate-CBD (anterior frontal cortex: p < 0.001, caudate: p = 0.001) and End-stage-CBD (anterior frontal cortex: p = 0.03, caudate: p = 0.01) as demonstrated by its higher neuronal-to-astrocytic plaque ratios in both anterior frontal cortex and caudate. We did not identify any difference in age at onset, any pathogenic tau mutation or concomitant pathologies that could have contributed to the rapid progression of these RP-CBD cases. Mild TDP-43 pathology was observed in three RP-CBD cases. All RP-CBD cases were men. The MAPT H2 haplotype, known to be protective, was identified in one RP-CBD case (17%) and 8 of the matched End-stage-CBD cases (67%). We conclude that RP-CBD is a distinct aggressive variant of corticobasal degeneration with characteristic neuropathological substrates resulting in a fulminant disease process as evident both clinically and pathologically. Biological factors such as genetic modifiers likely play a pivotal role in the RP-CBD variant and should be the subject of future research.


Assuntos
Doenças dos Gânglios da Base/patologia , Doenças Neurodegenerativas/patologia , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doenças dos Gânglios da Base/metabolismo , Córtex Cerebral/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/metabolismo
4.
Am J Hum Genet ; 98(4): 763-71, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27058447

RESUMO

Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.


Assuntos
Coreia/genética , Corpo Estriado/patologia , Mutação , Diester Fosfórico Hidrolases/genética , Sequência de Aminoácidos , Animais , Criança , Coreia/diagnóstico , Corpo Estriado/metabolismo , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Conformação Proteica , Alinhamento de Sequência , Transdução de Sinais , Adulto Jovem
5.
Hum Mol Genet ; 24(18): 5326-9, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26157024

RESUMO

Myoclonus-dystonia (M-D) is a very rare movement disorder, caused in ∼30-50% of cases by mutations in SGCE. The CACNA1B variant c.4166G>A; (p.R1389H) was recently reported as the likely causative mutation in a single 3-generation Dutch pedigree with five subjects affected by a unique dominant M-D syndrome and cardiac arrhythmias. In an attempt to replicate this finding, we assessed by direct sequencing the frequency of CACNA1B c.4166G>A; (p.R1389H) in a cohort of 520 M-D cases, in which SGCE mutations had been previously excluded. A total of 146 cases (28%) had a positive family history of M-D. The frequency of the variant was also assessed in 489 neurologically healthy controls and in publicly available data sets of genetic variation (1000 Genomes, Exome Variant Server and Exome Aggregation Consortium). The variant was detected in a single sporadic case with M-D, but in none of the 146 probands with familial M-D. Overall, the variant was present at comparable frequencies in M-D cases (1 out of 520; 0.19%) and healthy controls (1 out of 489; 0.2%). A similar frequency of the variant was also reported in all publicly available databases. These results do not support a causal association between the CACNA1B c.4166G>A; (p.R1389H) variant and M-D.


Assuntos
Substituição de Aminoácidos , Canais de Cálcio Tipo N/genética , Códon , Distúrbios Distônicos/epidemiologia , Distúrbios Distônicos/genética , Mutação , Alelos , Estudos de Coortes , Europa (Continente)/epidemiologia , Exoma , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino
6.
Mov Disord ; 32(2): 219-226, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28090684

RESUMO

BACKGROUND: A number of early features can precede the diagnosis of Parkinson's disease (PD). OBJECTIVE: To test an online, evidence-based algorithm to identify risk indicators of PD in the UK population. METHODS: Participants aged 60 to 80 years without PD completed an online survey and keyboard-tapping task annually over 3 years, and underwent smell tests and genotyping for glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) mutations. Risk scores were calculated based on the results of a systematic review of risk factors and early features of PD, and individuals were grouped into higher (above 15th centile), medium, and lower risk groups (below 85th centile). Previously defined indicators of increased risk of PD ("intermediate markers"), including smell loss, rapid eye movement-sleep behavior disorder, and finger-tapping speed, and incident PD were used as outcomes. The correlation of risk scores with intermediate markers and movement of individuals between risk groups was assessed each year and prospectively. Exploratory Cox regression analyses with incident PD as the dependent variable were performed. RESULTS: A total of 1323 participants were recruited at baseline and >79% completed assessments each year. Annual risk scores were correlated with intermediate markers of PD each year and baseline scores were correlated with intermediate markers during follow-up (all P values < 0.001). Incident PD diagnoses during follow-up were significantly associated with baseline risk score (hazard ratio = 4.39, P = .045). GBA variants or G2019S LRRK2 mutations were found in 47 participants, and the predictive power for incident PD was improved by the addition of genetic variants to risk scores. CONCLUSIONS: The online PREDICT-PD algorithm is a unique and simple method to identify indicators of PD risk. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Testes Genéticos/métodos , Doença de Parkinson/diagnóstico , Sintomas Prodrômicos , Medição de Risco/métodos , Assistência ao Convalescente , Idoso , Algoritmos , Feminino , Glucosilceramidase/genética , Humanos , Internet , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/genética , Fatores de Risco , Saliva
7.
Cell Rep ; 42(12): 113509, 2023 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-38019651

RESUMO

Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment (AIS), the site of action potential generation, could impact neuronal excitability in ALS human induced pluripotent stem cell (hiPSC) motor neurons. We find that early TDP-43 and C9orf72 hiPSC motor neurons show an increase in the length of the AIS and impaired activity-dependent AIS plasticity that is linked to abnormal homeostatic regulation of neuronal activity and intrinsic hyperexcitability. In turn, these hyperactive neurons drive increased spontaneous myofiber contractions of in vitro hiPSC motor units. In contrast, late hiPSC and postmortem ALS motor neurons show AIS shortening, and hiPSC motor neurons progress to hypoexcitability. At a molecular level, aberrant expression of the AIS master scaffolding protein ankyrin-G and AIS-specific voltage-gated sodium channels mirror these dynamic changes in AIS function and excitability. Our results point toward the AIS as an important site of dysfunction in ALS motor neurons.


Assuntos
Esclerose Lateral Amiotrófica , Segmento Inicial do Axônio , Células-Tronco Pluripotentes Induzidas , Humanos , Segmento Inicial do Axônio/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios Motores/metabolismo , Potenciais de Ação/fisiologia
8.
Adv Mater ; 34(18): e2110441, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35231133

RESUMO

Generating skeletal muscle tissue that mimics the cellular alignment, maturation, and function of native skeletal muscle is an ongoing challenge in disease modeling and regenerative therapies. Skeletal muscle cultures require extracellular guidance and mechanical support to stabilize contractile myofibers. Existing microfabrication-based solutions are limited by complex fabrication steps, low throughput, and challenges in measuring dynamic contractile function. Here, the synthesis and characterization of a new biobased nanohybrid elastomer, which is electrospun into aligned nanofiber sheets to mimic the skeletal muscle extracellular matrix, is presented. The polymer exhibits remarkable hyperelasticity well-matched to that of native skeletal muscle (≈11-50 kPa), with ultimate strain ≈1000%, and elastic modulus ≈25 kPa. Uniaxially aligned nanofibers guide myoblast alignment, enhance sarcomere formation, and promote a ≈32% increase in myotube fusion and ≈50% increase in myofiber maturation. The elastomer nanofibers stabilize optogenetically controlled human induced pluripotent stem cell derived skeletal myofibers. When activated by blue light, the myofiber-nanofiber hybrid constructs maintain a significantly higher (>200%) contraction velocity and specific force (>280%) compared to conventional culture methods. The engineered myofibers exhibit a power density of ≈35 W m-3 . This system is a promising new skeletal muscle tissue model for applications in muscular disease modeling, drug discovery, and muscle regeneration.


Assuntos
Células-Tronco Pluripotentes Induzidas , Nanofibras , Diferenciação Celular , Elastômeros , Humanos , Fibras Musculares Esqueléticas , Músculo Esquelético , Engenharia Tecidual/métodos , Alicerces Teciduais
9.
Parkinsonism Relat Disord ; 41: 37-43, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28511835

RESUMO

INTRODUCTION: ADCY5 mutations have been recently identified as an important cause of early-onset hyperkinetic movement disorders. The phenotypic spectrum associated with mutations in this gene is expanding. However, the ADCY5 mutational frequency in cohorts of paediatric patients with hyperkinetic movement disorders has not been evaluated. METHODS: We performed a screening of the entire ADCY5 coding sequence in 44 unrelated subjects with genetically undiagnosed childhood-onset hyperkinetic movement disorders, featuring chorea alone or in combination with myoclonus and dystonia. All patients had normal CSF analysis and brain imaging and were regularly followed-up in tertiary centers for paediatric movement disorders. RESULTS: We identified five unrelated subjects with ADCY5 mutations (11% of the cohort). Three carried the p. R418W mutation, one the p. R418Q and one the p. R418G mutation. Mutations arose de novo in four cases, while one patient inherited the mutation from his similarly affected father. All patients had delayed motor and/or language milestones with or without axial hypotonia and showed generalized chorea and dystonia, with prominent myoclonic jerks in one case. Episodic exacerbations of the baseline movement disorder were observed in most cases, being the first disease manifestation in two patients. The disease course was variable, from stability to spontaneous improvement during adolescence. CONCLUSION: Mutations in ADCY5 are responsible for a hyperkinetic movement disorder that can be preceded by episodic attacks before the movement disorder becomes persistent and is frequently misdiagnosed as dyskinetic cerebral palsy. A residual degree of neck hypotonia and a myopathy-like facial appearance are frequently observed in patients with ADCY5 mutations.


Assuntos
Adenilil Ciclases/genética , Deficiências do Desenvolvimento/etiologia , Transtornos dos Movimentos , Mutação/genética , Adolescente , Adulto , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/complicações , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/epidemiologia , Transtornos dos Movimentos/genética
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