Disease-related Huntingtin Seeding Activities in Cerebrospinal Fluids of Huntington's Disease Patients

Overview

Journal Sci Rep

Specialty Science

Date 2020 Nov 21

PMID 33219289

Citations 9

Authors

C Y Daniel Lee

Nan Wang

Koning Shen

Matthew Stricos

Peter Langfelder

Kristina H Cheon

Etty P Cortes

Harry V Vinters

Jean Paul Vonsattel

Nancy S Wexler

Robert Damoiseaux

Judith Frydman

X William Yang

Affiliations

Soon will be listed here.

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.

Citing Articles

Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin.

Oh J, Catherine C, Kim E, Min K, Chan Jeong H, Kim H Nat Commun. 2025; 16(1):737.

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The polyglutamine domain is the primary driver of seeding in huntingtin aggregation.

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Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease.

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