Fig. 3

Hypothetical mechanisms involved in GVB formation. Under physiological conditions, endocytic and autophagic cargo is transported to the soma, where it is degraded in lysosomes. Efficient lysosomal degradation is safeguarded by the lysosomal reformation cycle and the delivery of essential lysosomal proteins and hydrolases. Proteinopathy, such as tau pathology, leads to the formation of GVBs that have been identified as lysosomal structures based on the presence of a single limiting membrane, lysosomal transmembrane proteins, the hydrolase CTSD and a proteolytic activity marker. Yet, GVBs harbor a characteristic dense proteinaceous core distinguishing them from physiological lysosomes. This indicates that protein aggregation alters the lysosomal system in such a way that the GVB-type lysosomes are formed. Possible protein aggregation-induced mechanisms that may contribute to GVB formation are shown. See text for details