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.