ESCRT functions in autophagy and associated disease.
Mutations in the endosomal sorting complexes required for transport (ESCRT)-III subunit CHMP2B are associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both human neurodegenerative diseases characterized by accumulation of ubiquitinated proteins aggregates in affected neurons. The ESCRT proteins are known to be involved in diverse cellular processes such as mRNA transport, cytokinesis, transcriptional regulation and sorting of transmembrane proteins into the inner vesicles of the multivesicular body (MVB) during endocytosis. It was until recently not clear how ESCRT function may be involved in neurodegeneration. New findings in mammalian cells and in Drosophila melanogaster show that functional ESCRTs are required for efficient fusion of autophagic vesicles with the endocytic pathway and for degradation of autophagic cargo. Moreover, defective ESCRT function led to the accumulation of cytoplasmic protein aggregates containing ubiquitin, p62/Sequestosome-1 and TAR DNA binding protein 43 (TDP-43). Using cellular and Drosophila models for Huntington's disease it was also shown that reduced ESCRT levels inhibit clearance of expanded polyglutamine aggregates and aggravate their neurotoxic effect. These data indicate that efficient autophagic degradation requires functional MVBs and provides a possible explanation to the observed neurodegenerative phenotype seen in patients with CHMP2B mutations.
Rusten
Tor Erik
TE
Centre for Cancer Biomedicine, University of Oslo and Department of Biochemistry, The Norwegian Radium Hospital, Montebello, Oslo, Norway.
Simonsen
Anne
A
D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002490:Central Nervous System / Q000378:metabolism / Q000503:physiopathology; D004705:Endocytosis / Q000235:genetics*; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D021381:Protein Transport / Q000235:genetics; D011506:Proteins / Q000378:metabolism; D022161:Transport Vesicles / Q000235:genetics / Q000378:metabolism*
C503812:CHMP2B protein, human; D056827:Endosomal Sorting Complexes Required for Transport; D009419:Nerve Tissue Proteins; D011506:Proteins