During autophagy, the cell gobbles up its own internal components into membranous structures called autophagosomes, which fuse with multivesicular bodies (MVBs) before delivery to lysosomes, where the sequestered material is degraded. Autophagy is particularly important at times of cell stress and energy depletion, when the cell must recycle old organelles and cytoplasmic proteins to provide a source of amino acids. Even unstressed cells, however, probably clean house regularly using a low level of autophagy.
Those autophagy vesicles—the MVBs—were recently linked to a form of dementia. A family with frontotemporal dementia (FTD) was found to have mutations in an MVB-associated protein called CHMP2B. CHMP2B is a subunit of the ESCRT complexes, which sort ubiquitinated endocytosed proteins into MVBs for degradation in the lysosome. CHMP2B mutations have also been found in patients with amyotrophic lateral sclerosis (ALS). FTD and ALS are neurodegenerative diseases characterized by abnormal ubiquitin-positive protein deposits in affected neurons.
To investigate the molecular basis of disease in patients with CHMP2B mutations, Filimonenko and colleagues knocked down different ESCRT subunits or overexpressed CHMP2B mutants in cultured cells. Tracking the progress of autophagosomes in these cells revealed that fusion of MVBs with lysosomes was impaired. The resulting lack of lysosomal degradation caused ubiquitinated proteins to build up in the autophagic pathway and in the cytosol.
The autophagy-deficient cells seemed to be trying to compensate by ramping up a second protein–degradation pathway, headed by the proteasome. This was insufficient to compensate for the autophagy deficiency, however.
The authors also found that ESCRT depletion inhibited degradation of the expanded polyglutamine aggregates that are associated with Huntington's disease, indicating that MVBs are generally needed for both autophagic housekeeping duties and healthy neuronal function.