Lysosomal Dysfunction and Autophagy Blockade Contribute to MDMA-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells.

I-Hsun Li; Jui-Hu Shih; Ting-Yin Yeh; Hung-Che Lin; Ming-Hua Chen; Yuahn-Sieh Huang

doi:10.1021/acs.chemrestox.9b00437

Lysosomal Dysfunction and Autophagy Blockade Contribute to MDMA-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells.

I-Hsun Li, Jui-Hu Shih, Ting-Yin Yeh, Hung-Che Lin, Ming-Hua Chen, Yuahn-Sieh Huang

Chemical Research in Toxicology April 20, 2020 DOI: 10.1021/acs.chemrestox.9b00437 (opens in new tab)

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Study at a glance

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Characteristics	In vitro cell culture study Peer reviewed
Population	SH-SY5Y neuroblastoma cells and cultured cortical and serotonergic neurons
Intervention	MDMA
Topics	MDMA
Key points	MDMA decreased the activity of lysosomal cathepsins B and D and induced lysosomal swelling in SH-SY5Y cells and cultured cortical neurons, which the authors propose leads to autophagosome accumulation and blocked autophagic degradation. Inactivating cathepsins B and D mimicked MDMA-induced cell death and autophagy-lysosomal dysregulation, suggesting impaired lysosomal proteolysis contributes to MDMA neurotoxicity.

Abstract

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.

Comparable studies

Other preclinical and animal studies on MDMA, most cited first.

Study	Year	Design
Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context)	1987	Experimental study
3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain	1987	Animal experiment
Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells	2006	In vitro laboratory study
Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat Rats	1998	Experimental study
Altered Serotonin Innervation Patterns in the Forebrain of Monkeys Treated with (±)3,4-Methylenedioxymethamphetamine Seven Years Previously: Factors Influencing Abnormal Recovery Squirrel monkeys treated with MDMA	1999	Observational cohort

Citations in the library

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Caffeine and MDMA (ecstasy) exacerbate ER stress triggered by hyperthermia bioRxiv (Cold Spring Harbor Laboratory)

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