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

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...

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Veröffentlicht in:Scientific reports 2020-11, Vol.10 (1), p.20295-20295, Article 20295
Hauptverfasser: Lee, C. Y. Daniel, Wang, Nan, Shen, Koning, Stricos, Matthew, Langfelder, Peter, Cheon, Kristina H., Cortés, Etty P., Vinters, Harry V., Vonsattel, Jean Paul, Wexler, Nancy S., Damoiseaux, Robert, Frydman, Judith, Yang, X. William
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container_title Scientific reports
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creator Lee, C. Y. Daniel
Wang, Nan
Shen, Koning
Stricos, Matthew
Langfelder, Peter
Cheon, Kristina H.
Cortés, Etty P.
Vinters, Harry V.
Vonsattel, Jean Paul
Wexler, Nancy S.
Damoiseaux, Robert
Frydman, Judith
Yang, X. William
description 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.
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Y. Daniel ; Wang, Nan ; Shen, Koning ; Stricos, Matthew ; Langfelder, Peter ; Cheon, Kristina H. ; Cortés, Etty P. ; Vinters, Harry V. ; Vonsattel, Jean Paul ; Wexler, Nancy S. ; Damoiseaux, Robert ; Frydman, Judith ; Yang, X. William</creator><creatorcontrib>Lee, C. Y. Daniel ; Wang, Nan ; Shen, Koning ; Stricos, Matthew ; Langfelder, Peter ; Cheon, Kristina H. ; Cortés, Etty P. ; Vinters, Harry V. ; Vonsattel, Jean Paul ; Wexler, Nancy S. ; Damoiseaux, Robert ; Frydman, Judith ; Yang, X. William</creatorcontrib><description>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. 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Y. Daniel</au><au>Wang, Nan</au><au>Shen, Koning</au><au>Stricos, Matthew</au><au>Langfelder, Peter</au><au>Cheon, Kristina H.</au><au>Cortés, Etty P.</au><au>Vinters, Harry V.</au><au>Vonsattel, Jean Paul</au><au>Wexler, Nancy S.</au><au>Damoiseaux, Robert</au><au>Frydman, Judith</au><au>Yang, X. William</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Disease-related Huntingtin seeding activities in cerebrospinal fluids of Huntington’s disease patients</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2020-11-20</date><risdate>2020</risdate><volume>10</volume><issue>1</issue><spage>20295</spage><epage>20295</epage><pages>20295-20295</pages><artnum>20295</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>In Huntington’s disease (HD), the mutant Huntingtin (mHTT) is postulated to mediate template-based aggregation that can propagate across cells. 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This seeding activity can be ameliorated by targeting specific domain or proteostatic pathway of mHTT, providing novel insights into such pathological activities.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33219289</pmid><doi>10.1038/s41598-020-77164-1</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record>
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subjects 692/53/2421
692/617
692/699
692/699/375/1558
Adult
Aged
Aged, 80 and over
Alzheimer's disease
Antibodies
Brain - pathology
Cell Line
Cerebrospinal fluid
Cerebrospinal Fluid - metabolism
Exons - genetics
Female
Genes, Reporter - genetics
HSP40 Heat-Shock Proteins - genetics
HSP40 Heat-Shock Proteins - metabolism
Humanities and Social Sciences
Humans
Huntingtin
Huntingtin Protein - cerebrospinal fluid
Huntingtin Protein - genetics
Huntingtin Protein - metabolism
Huntington Disease - cerebrospinal fluid
Huntington Disease - genetics
Huntington Disease - pathology
Huntington's disease
Huntingtons disease
Intravital Microscopy
Male
Middle Aged
Molecular Chaperones - genetics
Molecular Chaperones - metabolism
multidisciplinary
Mutation
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neurology
Neuropathology
Patients
Polyproline
Protein Aggregation, Pathological - cerebrospinal fluid
Protein Aggregation, Pathological - genetics
Protein Aggregation, Pathological - pathology
Protein Domains - genetics
Protein Engineering
Protein Folding
Proteins
Science
Science (multidisciplinary)
Seeds
Species
title Disease-related Huntingtin seeding activities in cerebrospinal fluids of Huntington’s disease patients
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