PMID- 32186374
OWN - NLM
STAT- MEDLINE
DCOM- 20210702
LR  - 20210702
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Linking)
VI  - 33
IP  - 4
DP  - 2020 Apr 20
TI  - Lysosomal Dysfunction and Autophagy Blockade Contribute to MDMA-Induced 
      Neurotoxicity in SH-SY5Y Neuroblastoma Cells.
PG  - 903-914
LID - 10.1021/acs.chemrestox.9b00437 [doi]
AB  - Methylenedioxymethamphetamine (MDMA) is a psychostimulant with high abuse 
      potential and severe neurotoxicity. According to our previous study, MDMA 
      promotes autophagosome accumulation and contributes to cell death in cultured 
      cortical and serotonergic neurons. However, the detailed mechanism underlying 
      autophagy dysfunction remains unclear. Lysosomes play an important role in 
      autophagic degradation. The present study aimed to examine the role of lysosomal 
      function in autophagic flux in neuronal cultures exposed to MDMA. We showed that 
      MDMA induced enlarged vesicles that accumulate in SH-SY5Y neuroblastoma cells. In 
      addition, we demonstrated that MDMA stimulated dynamin-dependent but 
      clathrin-independent endocytosis, which might contribute to vacuole expansion. 
      Morphological and Western blot analyses revealed that MDMA induced lysosomal 
      swelling, whereas the activity of the lysosomal hydrolytic enzymes cathepsin B 
      and cathepsin D was decreased in SH-SY5Y and cultured cortical neurons, which 
      might lead to autophagosome accumulation and autophagic degradation blockage. 
      Intriguingly, inactivation of cathepsins B and D led to cell death and 
      autophagy-lysosomal dysregulation, which mimicked MDMA-induced neurotoxicity. 
      Consequently, impairment of lysosomal proteolysis and blockage of autophagy 
      degradation contributed to MDMA-induced neurotoxicity in neuronal cultures.
FAU - Li, I-Hsun
AU  - Li IH
AD  - Department of Pharmacy Practice, Tri-Service General Hospital, Taipei 114, 
      Taiwan.
AD  - School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan.
FAU - Shih, Jui-Hu
AU  - Shih JH
AD  - Department of Pharmacy Practice, Tri-Service General Hospital, Taipei 114, 
      Taiwan.
AD  - School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan.
FAU - Yeh, Ting-Yin
AU  - Yeh TY
AD  - Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, 
      Taiwan.
FAU - Lin, Hung-Che
AU  - Lin HC
AD  - Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, 
      National Defense Medical Center, Taipei 114, Taiwan.
FAU - Chen, Ming-Hua
AU  - Chen MH
AD  - Division of Neurology, Department of Medicine, Armed Forces Taoyuan General 
      Hospital, Taoyuan 325, Taiwan.
AD  - Department of Neurology, Tri-Service General Hospital, National Defense Medical 
      Center, Taipei, Taiwan.
FAU - Huang, Yuahn-Sieh
AU  - Huang YS
AUID- ORCID: 0000-0003-3527-6421
AD  - Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, 
      Taiwan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200327
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Autophagy/*drug effects
MH  - Cell Survival/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Lysosomes/*drug effects/metabolism/*pathology
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*toxicity
MH  - Neuroblastoma/*pathology
MH  - Neurons/*drug effects/metabolism/*pathology
MH  - Tumor Cells, Cultured
EDAT- 2020/03/19 06:00
MHDA- 2021/07/03 06:00
CRDT- 2020/03/19 06:00
PHST- 2020/03/19 06:00 [pubmed]
PHST- 2021/07/03 06:00 [medline]
PHST- 2020/03/19 06:00 [entrez]
AID - 10.1021/acs.chemrestox.9b00437 [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2020 Apr 20;33(4):903-914. doi: 10.1021/acs.chemrestox.9b00437. 
      Epub 2020 Mar 27.