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Published November 2021 | Supplemental Material + Published
Journal Article Open

Amplification of neurotoxic HTTex1 assemblies in human neurons


Huntington's disease (HD) is a genetically inherited neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) repeat in the exon-1 of huntingtin protein (HTT). The expanded polyQ enhances the amyloidogenic propensity of HTT exon 1 (HTTex1), which forms a heterogeneous mixture of assemblies with a broad neurotoxicity spectrum. While predominantly intracellular, monomeric and aggregated mutant HTT species are also present in the cerebrospinal fluids of HD patients, however, their biological properties are not well understood. To explore the role of extracellular mutant HTT in aggregation and toxicity, we investigated the uptake and amplification of recombinant HTTex1 assemblies in cell culture models. We find that small HTTex1 fibrils preferentially enter human neurons and trigger the amplification of neurotoxic assemblies; astrocytes or epithelial cells are not permissive. The amplification of HTTex1 in neurons depletes endogenous HTT protein with non-pathogenic polyQ repeat, activates apoptotic caspase-3 pathway and induces nuclear fragmentation. Using a panel of novel monoclonal antibodies and genetic mutation, we identified epitopes within the N-terminal 17 amino acids and proline-rich domain of HTTex1 to be critical in neural uptake and amplification. Synaptosome preparations from the brain homogenates of HD mice also contain mutant HTT species, which enter neurons and behave similar to small recombinant HTTex1 fibrils. These studies suggest that amyloidogenic extracellular mutant HTTex1 assemblies may preferentially enter neurons, propagate and promote neurodegeneration.

Additional Information

© 2021 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Received 20 July 2021, Revised 24 August 2021, Accepted 21 September 2021, Available online 24 September 2021. We are grateful to Dr. Dr. Alejandro Balazs at the Ragon Institute for providing the IgG2 cDNA backbone and Dr. Alysson Muotri at USCD for the IPSC neuronal progenitors. We are also thankful to Dr. Jenny Morton at the University of Cambridge, Dr. Ignacio Munoz-Sanjuan and Dr. Jonathan Bard at CHDI, and Dr. Jeannie Chen at USC for critical suggestions. Ethics approval. All animal experiments and care complied with federal regulations and were reviewed and approved by the California Institute of Technology Institutional Animal Care and Use Committee (IACUC), protocol#1776-19. Funding was provided by a CHDI award to AK (A-12890), CHDI award (A-12640) to RL and AK, and 1R01NS084345 to RL. Authors' contributions. AK conceived the idea and wrote the manuscript. AC, JMI, NKP, AR, TM performed the experiments. AK, AC, RL and JMI analyzed the data. RL edited the manuscript. All authors have read and approved the paper. Authors declare no competing interest.

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Supplemental Material - 1-s2.0-S0969996121002667-mmc1.pptx


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August 22, 2023
August 22, 2023