title: The functional analysis of the CHMP2B missense mutation associated with neurodegenerative diseases in the endo-lysosomal pathway.
abstract: Endosomal sorting complexes required for transport (ESCRTs) regulate a key sorting step of protein trafficking between endosomal compartments in lysosomal degradation. Interestingly, mutations in charged multivesicular body protein 2B (CHMP2B), which is a core subunit of ESCRT-III, have been identified in some neurodegenerative diseases. However, the cellular pathogenesis resulting from CHMP2B missense mutations is unclear. Furthermore, little is known about their functional analysis in post-mitotic neurons. In order to examine their cellular pathogenesis, we analyzed their effects in the endo-lysosomal pathway in post-mitotic neurons. Interestingly, of the missense mutant proteins, CHMP2B(T104N) mostly accumulated in the Rab5- and Rab7-positive endosomes and caused delayed degradation of EGFR as compared to CHMP2B(WT). Furthermore, CHMP2B(T104N) showed less association with Vps4 ATPase and was avidly associated with Snf7-2, a core component of ESCRT-III, suggesting that it may cause defects in the process of dissociation from ESCRT. Of the missense variants, CHMP2B(T104N) caused prominent accumulation of autophagosomes. However, neuronal cell survival was not dramatically affected by expression of CHMP2B(T104N). These findings suggested that, from among the various missense mutants, CHMP2B(T104N) was associated with relatively mild cellular pathogenesis in post-mitotic neurons. This study provided a better understanding of the cellular pathogenesis of neurodegenerative diseases associated with various missense mutations of CHMP2B as well as endocytic defects.
authors.affiliation: Department of Biotechnology, College of Life Science and Nano Technology, Hannam University, 461-6, Jeonmin-dong, Yuseong-gu, Daejeon 305-811, Republic of Korea.
authors.forename: Jeong-Ho
authors.initials: JH
authors.lastname: Han
authors.forename: Hyun-Hee
authors.initials: HH
authors.lastname: Ryu
authors.forename: Mi-Hee
authors.initials: MH
authors.lastname: Jun
authors.forename: Deok-Jin
authors.initials: DJ
authors.lastname: Jang
authors.forename: Jin-A
authors.initials: JA
authors.lastname: Lee
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000378:metabolism; D001343:Autophagy; D002470:Cell Survival; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008938:Mitosis; D020125:Mutation, Missense; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D059748:Proteolysis
chemical_list: C503812:CHMP2B protein, human; D056827:Endosomal Sorting Complexes Required for Transport; C512478:EGFR protein, human; D066246:ErbB Receptors; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C490304:VPS4B protein, human