02 May Novel Neuron Model Recapitulates Human 4R Tauopathy: Sheds Light on Potential Therapeutic Target
MedicalResearch.com Interview with:
Dr. Li Gan
Dr. Li Gan PhD
Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases
Brain and Mind Research Institute
Weill Cornell Medical College
Dr. Shiaoching Gong
Shiaoching Gong PhD
Helen and Robert Appel Alzheimer’s Disease Institute
Feil Family Brain and Mind Research Institute
Weill Cornell Medicine, New York, NY
MedicalResearch.com: What is the background for this study? Would you describe the process of making these neurons?
Response: Primary tauopathies are a group of progressive neurodegenerative diseases characterized by the pathological aggregation of 3R or 4R tau protein in neurons and/or glial cells, where 4R tauopathies are more common primary tauopathies. The exact pathological mechanisms remain elusive. There are currently no therapies available that can halt or reverse the spread of tau aggregates since the drug effects found in animal models are not always reproduced in human clinical trials. The development of tau therapies from human cells have become urgently needed. Induced human pluripotent stem cells (iPSCs) offer a unique model to better understand pathological mechanisms underlying human diseases and to develop human cell-based therapy. However, a major challenge to study 4R tauopathy is iPSC-derived neurons express very low levels of 4R Tau isoforms making it difficult to study 4R tauopathy and the mutations located in 4R Tau.
To address this need, we designed and engineered a robust human iPSC 4R tauopathy model using CRISPR/Cas9 technology. We first introduced specific mutations at the intron-exon 10 junctions and silent mutations within exon 10 to promote exon 10 inclusion, leading the increase of 4R isoforms expression in iPSC-derived neurons. Frontotemporal Dementia (FTD) mutation, P301S located in exon 10 is highly aggregation prone. To generate this human disease 4R tauopathy model, we then introduced this mutation to 4R iPSC to make it a 4RP301S iPSC line.
MedicalResearch.com: What are the main findings?
Response: The 4RP301S iPSC-derived neurons not only express pathological form of Tau protein in which progressive spread of tau aggregates could be observed within a few weeks upon seeding with Tau fibrils but also recapitulate some key features of the 4R tauopathy phenotypes including shared transcriptomic signatures, aberrant neuronal activity, autophagic body accumulation and endolysosomal pathway dysfunction. Unlike the slow and decades-long process of tau pathology in the human brain, these neurons significantly speed up the timeline for studying tau pathology.
MedicalResearch.com: How can these cells be potentially used in the diagnosis or treatment of tauopathies?
Response: The combination of CRISPRi/a system with iPSC technology enable unbiased and large-scale genetic perturbation screens to identify causative genes and pathways with desired phenotype of interest. Using CRISPRi system to knock down genes potentially associated with Tau pathology, we have identified 500 genes with significant effects on Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. UFMylation cascade is one of post-translational modifications involving the attachment of a small protein named UFM1 to lysine residue of its substrate proteins. The connection of this process toTau spread was previously unknown. We are very encouraged by the confirmation that inhibiting UFMylation blocked tau spread in both human neurons and mouse models, which may provide a deeper insight into Tau inclusions as well as new tools and directions for the development of treatments.
MedicalResearch.com: What recommendations do you have for future research as a results of this study?
Response: Success in achieving seeded Tau propagation in scalable and homogenous iPSC neurons provide a robust platform for future studies:
- Whole genome CRISPRi perturbation to identify new pathways to limit tau seeing and spreading.
- Develop HTS screens to identify compounds that reduce seeding or spreading as treatment for 4R tauopathy.
- Further develop to study co-pathologies (amyloid, alpha-synuclein TDP43), and interaction with glial cells
MedicalResearch.com: Is there anything else you would like to add? Any disclosures?
Response: Our human neuron model provides a powerful platform for disease modeling and helps understand the disease mechanisms that under the human physiological conditions, revealing previously unknown potential targets for drug development. Weill Cornell has filed a provisional patent to cover some of the findings.
Citation: Bravo CP, Giani AM, Perez JM, Zhao Z, Samelson A, Wong MY, Evangelisti A, Fan L, Pozner T, Mercedes M, Ye P, Patel T, Yarahmady A, Carling G, Lee VMY, Sharma M, Mok SA, Luo W, Zhao M, Kampmann M, Gong S, Gan L. Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. bioRxiv [Preprint]. 2023 Jun 22:2023.06.19.544278. doi: 10.1101/2023.06.19.544278. Update in: Cell. 2024 Mar 28;: PMID: 37745431; PMCID: PMC10516028.
https://www.cell.com/cell/fulltext/S0092-8674(24)00306-4
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Last Updated on May 3, 2024 by Marie Benz MD FAAD