ESCRT-III Dysfunction Causes Autophagosome Accumulation and Neurodegeneration

Abstract

Defects in the endosomal-lysosomal pathway have been implicated in a number of neurodegenerative disorders. A key step in the endocytic regulation of transmembrane proteins occurs in a subset of late-endosomal compartments known as multivesicular bodies (MVBs), whose formation is controlled by endosomal sorting complex required for transport (ESCRT). The roles of ESCRT in dendritic maintenance and neurodegeneration remain unknown. Here, we show that mSnf7-2, a key component of ESCRT-III, is highly expressed in most mammalian neurons. Loss of mSnf7-2 in mature cortical neurons caused retraction of dendrites and neuronal cell loss. mSnf7-2 binds to CHMP2B, another ESCRT-III subunit, in which a rare dominant mutation is associated with frontotemporal dementia linked to chromosome 3 (FTD3). Ectopic expression of the mutant protein CHMP2B(Intron5) also caused dendritic retraction prior to neurodegeneration. CHMP2B(Intron5) was associated more avidly than CHMP2B(WT) with mSnf7-2, resulting in sequestration of mSnf7-2 in ubiquitin-positive late-endosomal vesicles in cortical neurons. Moreover, loss of mSnf7-2 or CHMP2B(Intron5) expression caused the accumulation of autophagosomes in cortical neurons and flies. These findings indicate that ESCRT-III dysfunction is associated with the autophagy pathway, suggesting a novel neurodegeneration mechanism that may have important implications for understanding FTD and other age-dependent neurodegenerative diseases.

Overview of macroautophagy regulation in mammalian cells

“…It has recently been demonstrated that the multisubunit complex ESCRT III is needed for autophagosomes to fuse with MVB and lysosomes to generate amphisomes and autolysosomes, respectively [59][60][61]. ESCRT III dysfunction associated with the autophagic pathway may have important implications in neurodegenerative diseases (such as frontotemporal dementia and amyotrophic lateral sclerosis) [59,60]. The Hrs protein (hepatocyte growth factor-regulated tyrosine kinase substrate) plays a major role in endosomal sorting upstream of ESCRT complexes [58].…”

Autophagy and multivesicular bodies: two closely related partners

“…96,97 Recent publications have shown that autophagy degradation is abrogated in cells depleted of ESCRT subunits or in cells overexpressing a mutant of CHMP2B that caused an accumulation of ubiquitin-protein aggregates. 35,98 Indeed, loss of mSnf7-2, a key component of ESCRT-III that is highly expressed in neurons, caused autophagosome accumulation in cortical neurons, retraction of dendrites and neuronal cell loss. 98 Likewise, loss of ESCRT or Vps4 activity in Drosophila caused accumulation of autophagosomes, probably due to inhibition of fusion with compartments of the endocytic pathway.…”

“…35,98 Indeed, loss of mSnf7-2, a key component of ESCRT-III that is highly expressed in neurons, caused autophagosome accumulation in cortical neurons, retraction of dendrites and neuronal cell loss. 98 Likewise, loss of ESCRT or Vps4 activity in Drosophila caused accumulation of autophagosomes, probably due to inhibition of fusion with compartments of the endocytic pathway. 99 Furthermore, this ESCRT dysfunction increased the toxicity of polyglutamine aggregates in a model for Huntington's disease.…”

The Endosomal Na+/H+ Exchanger Contributes to Multivesicular Body Formation by Regulating the Recruitment of ESCRT-0 Vps27p to the Endosomal Membrane

“…In eukaryotic cells, the MVB pathway controls various important processes such as receptor down-regulation, antigen presentation, cytokinesis, retroviral budding, and autophagy (1)(2)(3)(4)(5)(6). In the budding yeast Saccharomyces cerevisiae, previous studies identified a number of genes involved in vacuolar protein sorting (VPS) (7,8).…”