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Updated: Jun 9, 2026
4D Imaging of Protein Aggregation in Live Cells
Published on: April 5, 2013
ATF3-dependent formation of inclusion bodies in polyQ-expressing human iPSC-derived neurons confers cellular
Walaa Oweis1,2, Malka Nissim-Rafinia1, Elad Dvir1
1Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, Israel.
Insights
In Huntington's disease (HD), polyglutamine (polyQ) inclusion bodies (IBs) protect neurons from stress-induced death. The ATF3 protein is crucial for forming these protective IBs in human cells.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG repeat expansions in the Huntingtin (HTT) gene.
- The resulting polyglutamine (polyQ) expansion in the HTT protein leads to misfolding and aggregation.
- The role of polyQ aggregates forming inclusion bodies (IBs) in HD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of polyQ inclusion bodies (IBs) in neuronal cell death in Huntington's disease models.
- To explore the involvement of ATF3 in the formation of polyQ IBs and its impact on cell survival.
Main Methods:
- Development of fluorescent induced pluripotent stem cell (iPSC)-based human neuronal models for polyQ-related disorders.
- Comparative analysis of cell death in neurons with and without polyQ inclusion bodies (IBs).
- Genetic manipulation, including ATF3 knockout, to assess its effect on IB formation and cell vulnerability.
Main Results:
- Polyglutamine (polyQ) inclusion bodies (IBs) were found to have a significant protective effect against cell death in iPSC-derived neurons.
- Knockout of ATF3 inhibited polyQ IB formation.
- Cells lacking ATF3 and polyQ IBs exhibited increased vulnerability to induced cellular stress.
Conclusions:
- Polyglutamine (polyQ) inclusion bodies (IBs) play a protective role against stress-induced cell death in human neuronal cells.
- ATF3 is identified as a key regulator of polyQ IB formation in human neural progenitor cells (NPCs).
- These findings highlight a novel protective mechanism in HD pathogenesis and identify ATF3 as a potential therapeutic target.
Abstract:
Huntington's disease (HD) is an incurable, neurodegenerative disorder. While the causative mutation - CAG expansions within the coding region of the Huntingtin (HTT) gene - has been identified over 30 years ago, the pathological mechanisms underlying HD are still not clear. The abnormal CAG track encodes a polyglutamine (polyQ) expanded protein, which leads to HTT protein misfolding. These polyQ aggregates can form insoluble inclusion bodies (IBs); however, whether IBs are protective or detrimental remains debatable. Here we developed fluorescent iPSC-based human neuronal models for polyQ-related disorders. Comparing cell death in IB+ and IB- iPSC-derived neurons, growing side-by-side, we demonstrate that polyQ IBs have a significant protective effect. Remarkably, knocking out ATF3 prevented polyQ-IB formation and rendered the cells more vulnerable to induced stress. Taken together, our results reveal ATF3's role in polyQ IB formation in human NPCs, and demonstrate that polyQ IBs protect cells from stress-induced death.
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