title: Exposure to ALS-FTD-CSF generates TDP-43 aggregates in glioblastoma cells through exosomes and TNTs-like structure.
abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent a continuum of devastating neurodegenerative diseases, characterized by transactive response DNA-binding protein of 43 kDa (TDP-43) aggregates accumulation throughout the nervous system. Despite rapidly emerging evidence suggesting the hypothesis of 'prion-like propagation' of TDP-43 positive inclusion in the regional spread of ALS symptoms, whether and how TDP-43 aggregates spread between cells is not clear. Herein, we established a cerebrospinal fluid (CSF)-cultured cell model to dissect mechanisms governing TDP-43 aggregates formation and propagation. Remarkably, intracellular TDP-43 mislocalization and aggregates were induced in the human glioma U251 cells following exposure to ALS-FTD-CSF but not ALS-CSF and normal control (NC) -CSF for 21 days. The exosomes derived from ALS-FTD-CSF were enriched in TDP-43 C-terminal fragments (CTFs). Incubation of ALS-FTD-CSF induced the increase of mislocated TDP-43 positive exosomes in U251 cells. We further demonstrated that exposure to ALS-FTD-CSF induced the generations of tunneling nanotubes (TNTs)-like structure and exosomes at different stages, which mediated the propagation of TDP-43 aggregates in the cultured U251 cells. Moreover, immunoblotting analyses revealed that abnormal activations of apoptosis and autophagy were induced in U251 cells, following incubation of ALS-CSF and ALS-FTD-CSF. Taken together, our data provide direct evidence that ALS-FTD-CSF has prion-like transmissible properties. TNTs-like structure and exosomes supply the routes for the transfer of TDP-43 aggregates, and selective inhibition of their over-generations may interrupt the progression of TDP-43 proteinopathy.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Xuebing
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Neurology, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China.|Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA.
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: College of Engineering, California State University, Los Angeles, CA, USA.
authors.forename: Robert K F
authors.initials: RK
authors.lastname: Teng
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Jingzheng
authors.initials: J
authors.lastname: Yin
authors.affiliation: Scott & White Neuroscience Institute, Texas A & M Health Science Center, College of Medicine, Temple, TX, USA.
authors.forename: Ekokobe
authors.initials: E
authors.lastname: Fonkem
authors.affiliation: Scott & White Neuroscience Institute, Texas A & M Health Science Center, College of Medicine, Temple, TX, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 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.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Wang
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000134:cerebrospinal fluid*; D017209:Apoptosis; D001343:Autophagy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D057180:Frontotemporal Dementia / Q000134:cerebrospinal fluid*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D043942:Nanotubes / Q000737:chemistry; D011328:Prions / Q000737:chemistry
chemical_list: D004268:DNA-Binding Proteins; D011328:Prions
keywords: ALS; FTD; TDP-43; exosomes; tunneling nanotubes