Fig. 9

Schematic depiction of endolysosomal pathway dysregulation in Huntington’s disease. a The endolysosomal pathway under normal conditions. Early endosomes mature into multivesicular bodies (MVBs) containing many intraluminal vesicles (ILVs). MVBs can either merge with the plasma membrane to release ILVs as exosomes or undergo lysosomal degradation. Macroautophagy (autophagy) starts with the formation of a phagophore to engulf cellular contents. Expansion and maturation of the phagophore gives rise to the double-membraned autophagosome. Autophagosomes can either fuse with lysosomes to form an autolysosome or can merge with MVBs to form an amphisome. Amphisomes are believed to either undergo exocytosis or fuse with lysosomes. Eventually, MVBs, autophagosomes and amphisomes fuse with lysosomes and their contents are degraded and recycled. b In HD, it is likely that HTT aggregates are engulfed by a phagophore into an autophagosome and then enter amphisomes through the fusion of MVBs and autophagosomes to form this hybrid organelle. Alternatively, aggregates could be taken up by MVBs. Organelles over-loaded with HTT aggregates may become dysfunctional and/or be targeted for further autophagy and degradation. In this process, exocytosis through MVBs and amphisomes could be reduced and lysosomal or autophagic dysfunction may occur. This would result in the accumulation of MVBs/amphisomes and autolysosome/residual bodies containing HTT aggregates that was observed in HD brain sections