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Oncotarget. 2015 Sep 15;6(27):24178-91.

Exposure to ALS-FTD-CSF generates TDP-43 aggregates in glioblastoma cells through exosomes and TNTs-like structure.

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Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Neurology, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA.
College of Engineering, California State University, Los Angeles, CA, USA.
Scott & White Neuroscience Institute, Texas A & M Health Science Center, College of Medicine, Temple, TX, USA.


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.


ALS; FTD; TDP-43; exosomes; tunneling nanotubes

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