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Sökning: WFRF:(van Gerpen Jay A)

  • Resultat 1-6 av 6
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2.
  • Ogaki, Kotaro, et al. (författare)
  • Multiple system atrophy and apolipoprotein E
  • 2018
  • Ingår i: Movement Disorders. - 0885-3185 .- 1531-8257. ; 33:4, s. 647-650
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes has been associated with the unique neuropathology of MSA. We hypothesized that apolipoprotein E, which is associated with neurodegeneration, may also play a role in the pathogenesis of MSA. Objective: This study evaluated genetic associations of Apolipoprotein E alleles with risk of MSA and -synuclein pathology, and also examined whether apolipoprotein E isoforms differentially affect -synuclein uptake in a oligodendrocyte cell.Methods: One hundred sixty-eight pathologically confirmed MSA patients, 89 clinically diagnosed MSA patients, and 1,277 control subjects were genotyped for Apolipoprotein E. Human oligodendrocyte cell lines were incubated with -synuclein and recombinant human apolipoprotein E, with internalized -synuclein imaged by confocal microscopy and cells analyzed by flow cytometry.Results: No significant association with risk of MSA or was observed for either Apolipoprotein E 2 or 4. -Synuclein burden was also not associated with Apolipoprotein E alleles in the pathologically confirmed patients. Interestingly, in our cell assays, apolipoprotein E 4 significantly reduced -synuclein uptake in the oligodendrocytic cell line.Conclusions: Despite differential effects of apolipoprotein E isoforms on -synuclein uptake in a human oligodendrocytic cell, we did not observe a significant association at the Apolipoprotein E locus with risk of MSA or -synuclein pathology.
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3.
  • Prudencio, Mercedes, et al. (författare)
  • Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3
  • 2020
  • Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242. ; 12:566
  • Tidskriftsartikel (refereegranskat)abstract
    • Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.
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4.
  • Rademakers, Rosa, et al. (författare)
  • Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids.
  • 2012
  • Ingår i: Nature genetics. - 1546-1718. ; 44:2, s. 200-5
  • Tidskriftsartikel (refereegranskat)abstract
    • Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.
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5.
  • Wray, Selina, et al. (författare)
  • Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research
  • 2012
  • Ingår i: PLoS ONE. - : Public Library of Science. - 1932-6203. ; 7:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
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6.
  • Sundal, Christina, et al. (författare)
  • MRI characteristics and scoring in HDLS due to CSF1R gene mutations.
  • 2012
  • Ingår i: Neurology. - 1526-632X. ; 79:6, s. 566-74
  • Tidskriftsartikel (refereegranskat)abstract
    • To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5.
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  • Resultat 1-6 av 6

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