1. Disease-related Huntingtin seeding activities in cerebrospinal fluids of Huntington's disease patients.
- Author
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Lee CYD, Wang N, Shen K, Stricos M, Langfelder P, Cheon KH, Cortés EP, Vinters HV, Vonsattel JP, Wexler NS, Damoiseaux R, Frydman J, and Yang XW
- Subjects
- Adult, Aged, Aged, 80 and over, Brain pathology, Cell Line, Exons genetics, Female, Genes, Reporter genetics, HSP40 Heat-Shock Proteins genetics, Humans, Huntingtin Protein cerebrospinal fluid, Huntingtin Protein genetics, Huntington Disease cerebrospinal fluid, Huntington Disease genetics, Intravital Microscopy, Male, Middle Aged, Molecular Chaperones genetics, Mutation, Nerve Tissue Proteins genetics, Protein Aggregation, Pathological cerebrospinal fluid, Protein Aggregation, Pathological genetics, Protein Domains genetics, Protein Engineering, Protein Folding, Cerebrospinal Fluid metabolism, HSP40 Heat-Shock Proteins metabolism, Huntingtin Protein metabolism, Huntington Disease pathology, Molecular Chaperones metabolism, Nerve Tissue Proteins metabolism, Protein Aggregation, Pathological pathology
- Abstract
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.
- Published
- 2020
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