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Hyperstimulation of macropinocytosis leads to lysosomal dysfunction and cell death during exposure to methamphetamine in differentiated SH-SY5Y cells.
MedLine Citation:
PMID:  22613348     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Although various cytotoxic effects on neuronal cells caused by methamphetamine (METH) have been investigated, the cellular and molecular mechanisms of METH-induced neurotoxicity remain to be elucidated. We previously reported that METH-induced cytomorphological effects on retinoic acid (RA)-differentiated SH-SY5Y human neuroblastoma cells involved macropinocytosis, which is an actin-dependent endocytic pathway. We also noted that hyperstimulation of this process might play an important role in the cytotoxicity of METH in neuronal cells. In this study, we investigated the molecular mechanisms as well as subsequent outcomes of macropinocytosis during METH treatment. It was found that macropinosomes formed upon exposure to METH were colocalized with constitutively active GFP-Ras (G12V) and GFP-Rac1 (Q61L). Furthermore, both Ras inhibitor, farnesylthiosalicylic acid (FTS), and Rac1 inhibitor, EHT1864, significantly inhibited the formation of macropinosomes, suggesting the involvement of these molecules. The expressions of lysosome-associated membrane proteins (lamps) gradually increased by METH in a time-dependent manner. In contrast, the proteolytic activation of cathepsin L, a marker of lysosomal function, was markedly suppressed by METH. METH-induced dysfunction of lysosomal enzyme as well as cell death was significantly attenuated by nocodazole, a microtube interfering reagent that inhibits the transport of vesicles, including macropinosome, to lysosomes. Our results indicate that METH has cytotoxic effects, at least in part, by inhibiting normal lysosomal function through Ras- and Rac1-mediated macropinocytosis in RA-differentiated SH-SY5Y cells.
Authors:
Akina Nara; Toshihiko Aki; Takeshi Funakoshi; Kana Unuma; Koichi Uemura
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-5-14
Journal Detail:
Title:  Brain research     Volume:  -     ISSN:  1872-6240     ISO Abbreviation:  -     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-5-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0045503     Medline TA:  Brain Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier B.V.
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