title: Chronic exposure to cerebrospinal fluid of multiple system atrophy in neuroblastoma and glioblastoma cells induces cytotoxicity via ER stress and autophagy activation.
abstract: 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.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurology, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Ma
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Junfang
authors.initials: J
authors.lastname: Teng
authors.affiliation: Department of Neurology, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Jiewen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, USA.
authors.forename: Erxi
authors.initials: E
authors.lastname: Wu
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.|Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, USA.
authors.forename: Xuebing
authors.initials: X
authors.lastname: Ding
mesh_terms: D000368:Aged; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001932:Brain Neoplasms / Q000134:cerebrospinal fluid* / Q000473:pathology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000473:pathology*; D005260:Female; D005909:Glioblastoma / Q000134:cerebrospinal fluid* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000134:cerebrospinal fluid*; D009447:Neuroblastoma / Q000134:cerebrospinal fluid* / Q000473:pathology; D011689:Purkinje Cells / Q000473:pathology; D013378:Substantia Nigra / Q000473:pathology
keywords: autophagy; endoplasmic reticulum stress; glioblastoma; multiple system atrophy; neuroblastoma