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Title | Autophagy preferentially degrades non-fibrillar polyQ aggregates. |
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Journal, issue, pages | Mol Cell, Vol. 84, Issue 10, Page 1980-11994.e8, Year 2024 |
Publish date | May 16, 2024 |
Authors | Dorothy Y Zhao / Felix J B Bäuerlein / Itika Saha / F Ulrich Hartl / Wolfgang Baumeister / Florian Wilfling / |
PubMed 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 ...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. |
External links | Mol Cell / PubMed:38759629 |
Methods | EM (tomography) |
Structure data | EMDB-18110: The fibrillar and amorphous states of polyQ Q97 EMDB-18114: phagophore in fibrillar polyQ EMDB-18115: phagophore and lysosomes with amorphous polyQ EMDB-18116: autolysosome, lysosome next to polyQ fibrils are empty EMDB-18117: autophagosome and autolysosomes are empty next to fibrillar polyQ EMDB-18118: Isolated autophagosome |
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