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1.
Brain Commun ; 3(4): fcab236, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34708205

RESUMO

Evidence indicates that common variants found in genome-wide association studies increase risk of disease through gene regulation via expression Quantitative Trait Loci. Using multiple genome-wide methods, we examined if Single Nucleotide Polymorphisms increase risk of Amyotrophic Lateral Sclerosis through expression Quantitative Trait Loci, and whether expression Quantitative Trait Loci expression is consistent across people who had Amyotrophic Lateral Sclerosis and those who did not. In combining public expression Quantitative Trait Loci data with Amyotrophic Lateral Sclerosis genome-wide association studies, we used Summary-data-based Mendelian Randomization to confirm that SCFD1 was the only gene that was genome-wide significant in mediating Amyotrophic Lateral Sclerosis risk via expression Quantitative Trait Loci (Summary-data-based Mendelian Randomization beta = 0.20, standard error = 0.04, P-value = 4.29 × 10-6). Using post-mortem motor cortex, we tested whether expression Quantitative Trait Loci showed significant differences in expression between Amyotrophic Lateral Sclerosis (n = 76) and controls (n = 25), genome-wide. Of 20 757 genes analysed, the two most significant expression Quantitative Trait Loci to show differential in expression between Amyotrophic Lateral Sclerosis and controls involve two known Amyotrophic Lateral Sclerosis genes (SCFD1 and VCP). Cis-acting SCFD1 expression Quantitative Trait Loci downstream of the gene showed significant differences in expression between Amyotrophic Lateral Sclerosis and controls (top expression Quantitative Trait Loci beta = 0.34, standard error = 0.063, P-value = 4.54 × 10-7). These SCFD1 expression Quantitative Trait Loci also significantly modified Amyotrophic Lateral Sclerosis survival (number of samples = 4265, hazard ratio = 1.11, 95% confidence interval = 1.05-1.17, P-value = 2.06 × 10-4) and act as an Amyotrophic Lateral Sclerosis trans-expression Quantitative Trait Loci hotspot for a wider network of genes enriched for SCFD1 function and Amyotrophic Lateral Sclerosis pathways. Using gene-set analyses, we found the genes that correlate with this trans-expression Quantitative Trait Loci hotspot significantly increase risk of Amyotrophic Lateral Sclerosis (beta = 0.247, standard deviation = 0.017, P = 0.001) and schizophrenia (beta = 0.263, standard deviation = 0.008, P-value = 1.18 × 10-5), a disease that genetically correlates with Amyotrophic Lateral Sclerosis. In summary, SCFD1 expression Quantitative Trait Loci are a major factor in Amyotrophic Lateral Sclerosis, not only influencing disease risk but are differentially expressed in post-mortem Amyotrophic Lateral Sclerosis. SCFD1 expression Quantitative Trait Loci show distinct expression profiles in Amyotrophic Lateral Sclerosis that correlate with a wider network of genes that also confer risk of the disease and modify the disease's duration.

2.
Mol Ther Methods Clin Dev ; 20: 508-519, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33614825

RESUMO

Oligodendrocyte dysfunction has been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive motor neuron loss. The failure of trophic support provided by oligodendrocytes is associated with a concomitant reduction in oligodendroglial monocarboxylate transporter 1 (MCT1) expression and is detrimental for the long-term survival of motor neuron axons. Therefore, we established an adeno-associated virus 9 (AAV9)-based platform by which MCT1 was targeted mostly to white matter oligodendrocytes to investigate whether this approach could provide a therapeutic benefit in the SOD1G93A mouse model of ALS. Despite good oligodendrocyte transduction and AAV-mediated MCT1 transgene expression, the disease outcome of SOD1G93A mice was not altered. Our study further increases our current understanding about the complex nature of oligodendrocyte pathology in ALS and provides valuable insights into the future development of therapeutic strategies to efficiently modulate these cells.

4.
Ann Neurol ; 89(4): 686-697, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33389754

RESUMO

OBJECTIVE: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency. METHODS: In this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data. RESULTS: The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63). INTERPRETATION: In our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686-697.


Assuntos
Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Dosagem de Genes , Humanos , Masculino , Reprodutibilidade dos Testes , Fatores de Risco , Índice de Gravidade de Doença , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Sequenciamento Completo do Genoma
5.
Brain Commun ; 2(2): fcaa064, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32954321

RESUMO

Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P = 3.33 × 10-7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.

6.
EMBO J ; 39(1): e101112, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31721251

RESUMO

Several neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia (SCA) are caused by non-coding nucleotide repeat expansions. Different pathogenic mechanisms may underlie these non-coding repeat expansion disorders. While gain-of-function mechanisms, such as toxicity associated with expression of repeat RNA or toxicity associated with repeat-associated non-ATG (RAN) products, are most frequently connected with these disorders, loss-of-function mechanisms have also been implicated. We review the different pathways that have been linked to non-coding repeat expansion disorders such as C9ORF72-linked ALS/frontotemporal dementia (FTD), myotonic dystrophy, fragile X tremor/ataxia syndrome (FXTAS), SCA, and Huntington's disease-like 2. We discuss modes of RNA toxicity focusing on the identity and the interacting partners of the toxic RNA species. Using the C9ORF72 ALS/FTD paradigm, we further explore the efforts and different methods used to disentangle RNA vs. RAN toxicity. Overall, we conclude that there is ample evidence for a role of RNA toxicity in non-coding repeat expansion diseases.


Assuntos
Esclerose Amiotrófica Lateral/patologia , Ataxia/patologia , Proteína C9orf72/genética , Expansão das Repetições de DNA/genética , Síndrome do Cromossomo X Frágil/patologia , Demência Frontotemporal/patologia , Distrofia Miotônica/patologia , Doenças Neurodegenerativas/patologia , RNA/toxicidade , Tremor/patologia , Esclerose Amiotrófica Lateral/genética , Ataxia/genética , Síndrome do Cromossomo X Frágil/genética , Demência Frontotemporal/genética , Humanos , Mutação , Distrofia Miotônica/genética , Doenças Neurodegenerativas/genética , RNA/genética , Tremor/genética
7.
Hum Mol Genet ; 29(4): 605-617, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-31814004

RESUMO

Worldwide, stroke is the main cause of long-term adult disability. After the initial insult, most patients undergo a subacute period with intense plasticity and rapid functional improvements. This period is followed by a chronic phase where recovery reaches a plateau that is only partially modifiable by rehabilitation. After experimental stroke, various subacute rehabilitation paradigms improve recovery. However, in order to reach the best possible outcome, a combination of plasticity-promoting strategies and rehabilitation might be necessary. EphA4 is a negative axonal guidance regulator during development. After experimental stroke, reduced EphA4 levels improve functional outcome with similar beneficial effects upon the inhibition of EphA4 downstream targets. In this study, we assessed the effectiveness of a basic enriched environment in the chronic phase after photothrombotic stroke in mice as well as the therapeutic potential of EphA4 targeted therapy followed by rehabilitation. Our findings show that environmental enrichment in the chronic phase improves functional outcome up to 2 months post-stroke. Although EphA4 levels increase after experimental stroke, subacute EphA4 inhibition followed by environmental enrichment does not further increase recovery. In conclusion, we show that environmental enrichment during the chronic phase of stroke improves functional outcome in mice with no synergistic effects of the used EphA4 targeted therapy.


Assuntos
Modelos Animais de Doenças , Fragmentos de Peptídeos/farmacologia , Receptor EphA4/antagonistas & inibidores , Recuperação de Função Fisiológica , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Fosforilação , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia
8.
Brain Commun ; 2(2): fcaa160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33977260

RESUMO

We studied the feasibility, safety, tolerability and pharmacokinetics of intracerebroventricular delivery of recombinant human vascular endothelial growth factor in patients with amyotrophic lateral sclerosis. In this phase I study in patients with amyotrophic lateral sclerosis, the study drug was delivered using an implantable programmable pump connected to a catheter inserted in the frontal horn of the lateral cerebral ventricle. A first cohort received open label vascular endothelial growth factor (0.2, 0.8 and 2 µg/day), a second cohort received placebo, 0.8 or 2 µg/day of study dug. After the 3-month study period, all patients could participate in an open label extension study. In total, 18 patients with amyotrophic lateral sclerosis, seen at the University Hospitals in Leuven were included. The surgical procedure was well tolerated in most patients. One patient had transient postoperative seizures, due to an ischemic lesion along the catheter tract. The first 3-month study period was completed by 15/18 patients. Administration of 2 µg/day vascular endothelial growth factor resulted in sustained detectable levels in cerebrospinal fluid. A pulmonary embolus occurred in 3 patients, in 1 patient in the first 3-month study, and in 2 patients during the open label extension study. The study drug was well tolerated in the other patients, for up to 6 years in the open label extension study. Our study shows that intracerebroventricular administration of 2 µg/day of vascular endothelial growth factor to patients with amyotrophic lateral sclerosis is feasible, results in detectable cerebrospinal fluid levels and is well tolerated in most patients. The most common serious adverse event was a pulmonary embolus.

9.
Alzheimers Res Ther ; 11(1): 102, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831046

RESUMO

BACKGROUND: EphA4 is a receptor of the ephrin system regulating spine morphology and plasticity in the brain. These processes are pivotal in the pathophysiology of Alzheimer's disease (AD), characterized by synapse dysfunction and loss, and the progressive loss of memory and other cognitive functions. Reduced EphA4 signaling has been shown to rescue beta-amyloid-induced dendritic spine loss and long-term potentiation (LTP) deficits in cultured hippocampal slices and primary hippocampal cultures. In this study, we investigated whether EphA4 ablation might preserve synapse function and ameliorate cognitive performance in the APPPS1 transgenic mouse model of AD. METHODS: A postnatal genetic ablation of EphA4 in the forebrain was established in the APPPS1 mouse model of AD, followed by a battery of cognitive tests at 9 months of age to investigate cognitive function upon EphA4 loss. A Golgi-Cox staining was used to explore alterations in dendritic spine density and morphology in the CA1 region of the hippocampus. RESULTS: Upon EphA4 loss in APPPS1 mice, we observed improved social memory in the preference for social novelty test without affecting other cognitive functions. Dendritic spine analysis revealed altered synapse morphology as characterized by increased dendritic spine length and head width. These modifications were independent of hippocampal plaque load and beta-amyloid peptide levels since these were similar in mice with normal versus reduced levels of EphA4. CONCLUSION: Loss of EphA4 improved social memory in a mouse model of Alzheimer's disease in association with alterations in spine morphology.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Comportamento Animal/fisiologia , Espinhas Dendríticas/metabolismo , Hipocampo/metabolismo , Memória/fisiologia , Receptor EphA4/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Forma Celular/genética , Espinhas Dendríticas/patologia , Modelos Animais de Doenças , Hipocampo/patologia , Camundongos , Camundongos Transgênicos , Presenilina-1/genética , Receptor EphA4/metabolismo , Sinapses/metabolismo , Sinapses/patologia
10.
Front Neurosci ; 13: 1233, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803009

RESUMO

EphA4 is a receptor of the Eph-ephrin system, which plays an important role in axon guidance during development. Previously, we identified EphA4 as a genetic modifier of amyotrophic lateral sclerosis (ALS) in both zebrafish and rodent models, via modulation of the intrinsic vulnerability, and re-sprouting capacity of motor neurons. Moreover, loss of EphA4 rescued the motor axon phenotype in a zebrafish model of spinal muscular atrophy (SMA). Similar to ALS, SMA is a neurodegenerative disorder affecting spinal motor neurons resulting in neuromuscular junction (NMJ) denervation, muscle atrophy and paralysis. In this study, we investigated the disease modifying potential of reduced EphA4 protein levels in the SMNΔ7 mouse model for severe SMA. Reduction of EphA4 did not improve motor function, survival, motor neuron survival or NMJ innervation. Our data suggest that either lowering EphA4 has limited therapeutic potential in SMA or that the clinical severity hampers the potential beneficial role of EphA4 reduction in this mouse model for SMA.

11.
Sci Rep ; 9(1): 14112, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575928

RESUMO

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons resulting in severe neurological symptoms. Previous findings of our lab suggested that the axonal guidance tyrosine-kinase receptor EphA4 is an ALS disease-modifying gene. Reduction of EphA4 from developmental stages onwards rescued a motor neuron phenotype in zebrafish, and heterozygous deletion before birth in the SOD1G93A mouse model of ALS resulted in improved survival. Here, we aimed to gain more insights in the cell-specific role of decreasing EphA4 expression in addition to timing and amount of EphA4 reduction. To evaluate the therapeutic potential of lowering EphA4 later in life, we ubiquitously reduced EphA4 levels to 50% in SOD1G93A mice at 60 days of age, which did not modify disease parameters. Even further lowering EphA4 levels ubiquitously or in neurons, did not improve disease onset or survival. These findings suggest that lowering EphA4 as target in ALS may suffer from a complex therapeutic time window. In addition, the complexity of the Eph-ephrin signalling system may also possibly limit the therapeutic potential of such an approach in ALS. We suggest here that a specific EphA4 knockdown in adulthood may have a limited therapeutic potential for ALS.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Receptor EphA4/metabolismo , Animais , Modelos Animais de Doenças , Heterozigoto , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Motores/metabolismo , Fenótipo , Transdução de Sinais/fisiologia , Superóxido Dismutase-1/metabolismo , Peixe-Zebra/metabolismo
12.
Acta Neuropathol Commun ; 7(1): 114, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300041

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the brainstem, spinal cord and motor cortex. ALS is characterized by genetic and clinical heterogeneity, suggesting the existence of genetic factors that modify the phenotypic expression of the disease. We previously identified the axonal guidance EphA4 receptor, member of the Eph-ephrin system, as an ALS disease-modifying factor. EphA4 genetic inhibition rescued the motor neuron phenotype in zebrafish and a rodent model of ALS. Preventing ligands from binding to the EphA4 receptor also successfully improved disease, suggesting a role for EphA4 ligands in ALS. One particular ligand, ephrin-A5, is upregulated in reactive astrocytes after acute neuronal injury and inhibits axonal regeneration. Moreover, it plays a role during development in the correct pathfinding of motor axons towards their target limb muscles. We hypothesized that a constitutive reduction of ephrin-A5 signalling would benefit disease progression in a rodent model for ALS. We discovered that in the spinal cord of control and symptomatic ALS mice ephrin-A5 was predominantly expressed in neurons. Surprisingly, reduction of ephrin-A5 levels in SOD1G93A mice accelerated disease progression and reduced survival without affecting disease onset, motor neuron numbers or innervated neuromuscular junctions in symptomatic mice. These findings suggest ephrin-A5 as a modifier of disease progression that might play a role in the later stages of the disease. Similarly, we identified a more aggressive disease progression in patients with lower ephrin-A5 protein levels in the cerebrospinal fluid without modifying disease onset. In summary, we identified reduced expression of ephrin-A5 to accelerate disease progression in a mouse model of ALS as well as in humans. Combined with our previous findings on the role of EphA4 in ALS our current data suggests different contribution for various members of the Eph-ephrin system in the pathophysiology of a motor neuron disease.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Progressão da Doença , Efrina-A5/deficiência , Adulto , Idoso , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Animais , Efrina-A5/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Superóxido Dismutase-1/genética
13.
Sci Rep ; 9(1): 5931, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30976013

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 1 in ~350 individuals. Genetic association studies have established ALS as a multifactorial disease with heritability estimated at ~61%, and recent studies show a prominent role for rare variation in its genetic architecture. To identify rare variants associated with disease onset we performed exome array genotyping in 4,244 cases and 3,106 controls from European cohorts. In this largest exome-wide study of rare variants in ALS to date, we performed single-variant association testing, gene-based burden, and exome-wide individual set-unique burden (ISUB) testing to identify single or aggregated rare variation that modifies disease risk. In single-variant testing no variants reached exome-wide significance, likely due to limited statistical power. Gene-based burden testing of rare non-synonymous and loss-of-function variants showed NEK1 as the top associated gene. ISUB analysis did not show an increased exome-wide burden of deleterious variants in patients, possibly suggesting a more region-specific role for rare variation. Complete summary statistics are released publicly. This study did not implicate new risk loci, emphasizing the immediate need for future large-scale collaborations in ALS that will expand available sample sizes, increase genome coverage, and improve our ability to detect rare variants associated to ALS.


Assuntos
Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Exoma/genética , Marcadores Genéticos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Estudos de Associação Genética , Genótipo , Humanos , Fenótipo , Sequenciamento Completo do Exoma
15.
Cell Rep ; 26(9): 2298-2306.e5, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30811981

RESUMO

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport, and protein homeostasis. We report ALS-causing mutations within the gene encoding the glycosyltransferase GLT8D1. Exome sequencing in an autosomal-dominant ALS pedigree identified p.R92C mutations in GLT8D1, which co-segregate with disease. Sequencing of local and international cohorts demonstrated significant ALS association in the same exon, including additional rare deleterious mutations in conserved amino acids. Mutations are associated with the substrate binding site, and both R92C and G78W changes impair GLT8D1 enzyme activity. Mutated GLT8D1 exhibits in vitro cytotoxicity and induces motor deficits in zebrafish consistent with ALS. Relative toxicity of mutations in model systems mirrors clinical severity. In conclusion, we have linked ALS pathophysiology to inherited mutations that diminish the activity of a glycosyltransferase enzyme.


Assuntos
Esclerose Amiotrófica Lateral/genética , Glicosiltransferases/genética , Mutação , Esclerose Amiotrófica Lateral/diagnóstico , Animais , Linhagem Celular , Sobrevivência Celular , Éxons , Feminino , Técnicas de Silenciamento de Genes , Glicosiltransferases/metabolismo , Complexo de Golgi/enzimologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neurônios/enzimologia , Domínios Proteicos/genética , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética
16.
J Peripher Nerv Syst ; 24(1): 48-55, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30672091

RESUMO

Intravenous immunoglobulin (IVIG) is a potential therapy for chronic inflammatory demyelinating polyneuropathy (CIDP). To investigate the efficacy and safety of the IVIG IgPro10 (Privigen) for treatment of CIDP, results from Privigen Impact on Mobility and Autonomy (PRIMA), a prospective, open-label, single-arm study of IVIG in immunoglobulin (Ig)-naïve or IVIG pre-treated subjects (NCT01184846, n = 28) and Polyneuropathy And Treatment with Hizentra (PATH), a double-blind, randomized study including an open-label, single-arm IVIG phase in IVIG pre-treated subjects (NCT01545076, IVIG restabilization phase n = 207) were analyzed separately and together (n = 235). Efficacy assessments included change in adjusted inflammatory neuropathy cause and treatment (INCAT) score, grip strength and Medical Research Council (MRC) sum score. Adverse drug reactions (ADRs) and ADRs/infusion were recorded. Adjusted INCAT response rate was 60.7% in all PRIMA subjects at Week 25 (76.9% in IVIG pre-treated subjects) and 72.9% in PATH. In the pooled cohort (n = 235), INCAT response rate was 71.5%; median time to INCAT improvement was 4.3 weeks. No clear demographic differences were noticed between early (responding before Week 7, n = 148) and late responders (n = 21). In the pooled cohort, median change from baseline to last observation was -1.0 (interquartile range -2.0; 0.0) point for INCAT score; +8.0 (0.0; 20.0) kPa for maximum grip strength; +3.0 (1.0; 7.0) points for MRC sum score. In the pooled cohort, 271 ADRs were reported in 105 subjects (44.7%), a rate of 0.144 ADRs per infusion. This analysis confirms the efficacy and safety of IgPro10, a recently FDA-approved IVIG for CIDP, in a population of mainly pre-treated subjects with CIDP [Correction added on 14 March 2019 after first online publication: the INCAT response rate has been corrected.].


Assuntos
Imunoglobulinas Intravenosas/farmacologia , Fatores Imunológicos/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Europa (Continente) , Feminino , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Fatores Imunológicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
17.
Protein Eng Des Sel ; 32(10): 443-457, 2019 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-32399571

RESUMO

The accumulation of toxic protein aggregates is thought to play a key role in a range of degenerative pathologies, but it remains unclear why aggregation of polypeptides into non-native assemblies is toxic and why cellular clearance pathways offer ineffective protection. We here study the A4V mutant of SOD1, which forms toxic aggregates in motor neurons of patients with familial amyotrophic lateral sclerosis (ALS). A comparison of the location of aggregation prone regions (APRs) and Hsp70 binding sites in the denatured state of SOD1 reveals that ALS-associated mutations promote exposure of the APRs more than the strongest Hsc/Hsp70 binding site that we could detect. Mutations designed to increase the exposure of this Hsp70 interaction site in the denatured state promote aggregation but also display an increased interaction with Hsp70 chaperones. Depending on the cell type, in vitro this resulted in cellular inclusion body formation or increased clearance, accompanied with a suppression of cytotoxicity. The latter was also observed in a zebrafish model in vivo. Our results suggest that the uncontrolled accumulation of toxic SOD1A4V aggregates results from insufficient detection by the cellular surveillance network.


Assuntos
Esclerose Amiotrófica Lateral/genética , Proteínas de Choque Térmico HSP70/metabolismo , Mutação , Engenharia de Proteínas , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Sítios de Ligação , Humanos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Superóxido Dismutase-1/química
18.
Neurobiol Aging ; 74: 234.e9-234.e15, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30342764

RESUMO

NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10-5). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS.


Assuntos
Esclerose Amiotrófica Lateral/genética , Expansão das Repetições de DNA/genética , Estudos de Associação Genética , Proteínas de Membrana/genética , Estudos de Coortes , Feminino , Humanos , Internacionalidade , Modelos Logísticos , Masculino , Metanálise como Assunto , Peptídeos/genética
19.
Hum Mol Genet ; 27(23): 4103-4116, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30379317

RESUMO

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases characterized by the progressive loss of specific groups of neurons. Due to clinical, genetic and pathological overlap, both diseases are considered as the extremes of one disease spectrum and in a number of ALS and FTD patients, fused in sarcoma (FUS) aggregates are present. Even in families with a monogenetic disease cause, a striking variability is observed in disease presentation. This suggests the presence of important modifying genes. The identification of disease-modifying genes will contribute to defining clear therapeutic targets and to understanding the pathways involved in motor neuron death. In this study, we established a novel in vivo screening platform in which new modifying genes of FUS toxicity can be identified. Expression of human FUS induced the selective apoptosis of crustacean cardioactive peptide (CCAP) neurons from the ventral nerve cord of fruit flies. No defects in the development of these neurons were observed nor were the regulatory CCAP neurons from the brain affected. We used the number of CCAP neurons from the ventral nerve cord as an in vivo read-out for FUS toxicity in neurons. Via a targeted screen, we discovered a potent modifying role of proteins involved in nucleocytoplasmic transport. Downregulation of Nucleoporin 154 and Exportin1 (XPO1) prevented FUS-induced neurotoxicity. Moreover, we show that XPO1 interacted with FUS. Silencing XPO1 significantly reduced the propensity of FUS to form inclusions upon stress. Taken together, our findings point to an important role of nucleocytoplasmic transport proteins in FUS-induced ALS/FTD.


Assuntos
Esclerose Amiotrófica Lateral/genética , Demência Frontotemporal/genética , Carioferinas/genética , Neuropeptídeos/genética , Proteína FUS de Ligação a RNA/genética , Receptores Citoplasmáticos e Nucleares/genética , Esclerose Amiotrófica Lateral/fisiopatologia , Animais , Animais Geneticamente Modificados/genética , Apoptose/genética , Drosophila/genética , Proteínas de Drosophila/genética , Feminino , Demência Frontotemporal/fisiopatologia , Regulação da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/genética , Humanos , Masculino , Mutação , Neurônios/patologia , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Agregação Patológica de Proteínas/genética
20.
Mol Neurodegener ; 13(1): 55, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30326935

RESUMO

BACKGROUND: TAR DNA binding protein 43 (TDP-43) is the main disease protein in most patients with amyotrophic lateral sclerosis (ALS) and about 50% of patients with frontotemporal dementia (FTD). TDP-43 pathology is not restricted to patients with missense mutations in TARDBP, the gene encoding TDP-43, but also occurs in ALS/FTD patients without known genetic cause or in patients with various other ALS/FTD gene mutations. Mutations in progranulin (GRN), which result in a reduction of ~ 50% of progranulin protein (PGRN) levels, cause FTD with TDP-43 pathology. How loss of PGRN leads to TDP-43 pathology and whether or not PGRN expression protects against TDP-43-induced neurodegeneration is not yet clear. METHODS: We studied the effect of PGRN on the neurodegenerative phenotype in TDP-43(A315T) mice. RESULTS: PGRN reduced the levels of insoluble TDP-43 and histology of the spinal cord revealed a protective effect of PGRN on the loss of large axon fibers in the lateral horn, the most severely affected fiber pool in this mouse model. Overexpression of PGRN significantly slowed down disease progression, extending the median survival by approximately 130 days. A transcriptome analysis did not point towards a single pathway affected by PGRN, but rather towards a pleiotropic effect on different pathways. CONCLUSION: Our findings reveal an important role of PGRN in attenuating mutant TDP-43-induced neurodegeneration.


Assuntos
Esclerose Amiotrófica Lateral/mortalidade , Axônios/efeitos dos fármacos , Proteínas de Ligação a DNA/efeitos dos fármacos , Demência Frontotemporal/mortalidade , Mutação/genética , Progranulinas/farmacologia , Animais , Axônios/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Camundongos Transgênicos , Medula Espinal/metabolismo , Medula Espinal/patologia
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