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Journal Article

Autophagy preferentially degrades non-fibrillar polyQ aggregates

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Zhao,  Dorothy Y.       
Max Planck Institute of Biochemistry, Molecular Machines and Signaling, Martinsried, Germany;
Max Planck Institute of Biochemistry, Molecular Structural Biology, 82152 Martinsried, Germany;
Research Group Mechanisms of Cellular Quality Control, Max Planck Institute of Biophysics, Max Planck Society;

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Wilfling,  Florian       
Max Planck Institute of Biochemistry, Molecular Machines and Signaling, Martinsried, Germany;
Max Planck Institute of Biochemistry, Molecular Structural Biology, 82152 Martinsried, Germany;
Research Group Mechanisms of Cellular Quality Control, Max Planck Institute of Biophysics, Max Planck Society;
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA;

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Citation

Zhao, D. Y., Bäuerlein, F. J. B., Saha, I., Hartl, F. U., Baumeister, W., & Wilfling, F. (2024). Autophagy preferentially degrades non-fibrillar polyQ aggregates. Molecular Cell, 84(10), 1980-1994.e8. doi:10.1016/j.molcel.2024.04.018.


Cite as: https://hdl.handle.net/21.11116/0000-000F-4EC0-1
Abstract
Aggregation of proteins containing expanded polyglutamine (polyQ) repeats is the cytopathologic hallmark of a group of dominantly inherited neurodegenerative diseases, including Huntington's disease (HD). Huntingtin (Htt), the disease protein of HD, forms amyloid-like fibrils by liquid-to-solid phase transition. Macroautophagy has been proposed to clear polyQ aggregates, but the efficiency of aggrephagy is limited. Here, we used cryo-electron tomography to visualize the interactions of autophagosomes with polyQ aggregates in cultured cells in situ. We found that an amorphous aggregate phase exists next to the radially organized polyQ fibrils. Autophagosomes preferentially engulfed this amorphous material, mediated by interactions between the autophagy receptor p62/SQSTM1 and the non-fibrillar aggregate surface. In contrast, amyloid fibrils excluded p62 and evaded clearance, resulting in trapping of autophagic structures. These results suggest that the limited efficiency of autophagy in clearing polyQ aggregates is due to the inability of autophagosomes to interact productively with the non-deformable, fibrillar disease aggregates.