Disease-related Huntingtin seeding activities in cerebrospinal fluids of Huntington's disease patients.

Autor: Lee CYD; Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA.; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA., Wang N; Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA.; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA., Shen K; Department of Biology and BioX Program, Stanford University, Stanford, CA, USA.; Department of Molecular and Cell Biology, UC Berkeley, Berkeley, CA, USA., Stricos M; Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA.; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA., Langfelder P; Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA.; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA., Cheon KH; Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA.; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA., Cortés EP; Division of Aging and Dementia, Department of Neurology, Columbia University Medical Center, New York, NY, USA., Vinters HV; Department of Pathology and Laboratory Medicine, Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA., Vonsattel JP; Division of Aging and Dementia, Department of Neurology, Columbia University Medical Center, New York, NY, USA., Wexler NS; Departments of Neurology and Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA.; Hereditary Disease Foundation, New York, NY, USA., Damoiseaux R; California NanoSystems Institute, University of California, Los Angeles, CA, USA.; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA., Frydman J; Department of Biology and BioX Program, Stanford University, Stanford, CA, USA., Yang XW; Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, USA. xwyang@mednet.ucla.edu.; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. xwyang@mednet.ucla.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2020 Nov 20; Vol. 10 (1), pp. 20295. Date of Electronic Publication: 2020 Nov 20.
DOI: 10.1038/s41598-020-77164-1
Abstrakt: In Huntington's disease (HD), the mutant Huntingtin (mHTT) is postulated to mediate template-based aggregation that can propagate across cells. It has been difficult to quantitatively detect such pathological seeding activities in patient biosamples, e.g. cerebrospinal fluids (CSF), and study their correlation with the disease manifestation. Here we developed a cell line expressing a domain-engineered mHTT-exon 1 reporter, which showed remarkably high sensitivity and specificity in detecting mHTT seeding species in HD patient biosamples. We showed that the seeding-competent mHTT species in HD CSF are significantly elevated upon disease onset and with the progression of neuropathological grades. Mechanistically, we showed that mHTT seeding activities in patient CSF could be ameliorated by the overexpression of chaperone DNAJB6 and by antibodies against the polyproline domain of mHTT. Together, our study developed a selective and scalable cell-based tool to investigate mHTT seeding activities in HD CSF, and demonstrated that the CSF mHTT seeding species are significantly associated with certain disease states. This seeding activity can be ameliorated by targeting specific domain or proteostatic pathway of mHTT, providing novel insights into such pathological activities.
Databáze: MEDLINE
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