Chronic exposure to cerebrospinal fluid of multiple system atrophy in neuroblastoma and glioblastoma cells induces cytotoxicity via ER stress and autophagy activation
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Xuejing Wang1,*, Mingming Ma2,*, Junfang Teng1, Jiewen Zhang2, Shuang Zhou3, Ying Zhang3, Erxi Wu3, Xuebing Ding1,3
1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
2Department of Neurology, People’s Hospital of Zhengzhou University, Zhengzhou, Henan, China
3Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, USA
*These authors have contributed equally to this work
Xuebing Ding, e-mail: email@example.com
Erxi Wu, e-mail: Erxi.firstname.lastname@example.org
Keywords: multiple system atrophy, neuroblastoma, glioblastoma, endoplasmic reticulum stress, autophagy
Received: February 20, 2015 Accepted: April 08, 2015 Published: April 20, 2015
Oncogenesis and neurodegeneration share many common pathogenic pathways, involved in endoplastic reticulum (ER) stress, autophagy, DNA repair, and oxidative stress. However, mechanisms of cross-talking between oncogenesis and neurodegeneration are still unknown. Characterized by abnormal accumulation of α-synuclein (α-syn) aggregates in central nervous system (CNS), multiple system atrophy (MSA) is classified as α-synucleinopathy. Rapidly emerging evidence suggests that ‘prion-like propagation’ of α-syn aggregates in the regional spread of CNS leads to the progression of α-synucleinopathy. Whether cerebrospinal fluid (CSF) has deteriorating effects on neurogenic tumor cells and is involved in progression of α-synucleinopathy has not been explored. Here, we first show the cytotoxic effects of MSA-CSF on the neuroblastoma and glioblastoma cells and its underlying mechanism in vitro. Remarkably, MSA-CSF induced cytotoxicity via activating ER stress-associated apoptosis and autophagy in both SH-SY5Y and U251 cells. The result from in vivo systematic neuropathological analysis reveals that abnormally activated ER stress and autophagy were confined to substantia nigra and cerebellum in mouse CNS following MSA-CSF treatment. Specifically, dopamine neurons in substantia nigra and Purkinje cells in cerebellum cortex were degenerated in MSA-CSF-injected mice. Altogether, these findings demonstrate that MSA-CSF exerts cytotoxicities on nervous system neoplasms and accelerates the progression of synucleinopathies.
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