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Sci Rep DOI:10.1038/s41598-018-34759-z

Aggregated SOD1 causes selective death of cultured human motor neurons.

Publication TypeJournal Article
Year of Publication2018
AuthorsBenkler, C, O'Neil, AL, Slepian, S, Qian, F, Weinreb, PH, Rubin, LL
JournalSci Rep
Volume8
Issue1
Pages16393
Date Published2018 Nov 06
ISSN2045-2322
Abstract

Most human neurodegenerative diseases share a phenotype of neuronal protein aggregation. In Amyotrophic Lateral Sclerosis (ALS), the abundant protein superoxide dismutase (SOD1) or the TAR-DNA binding protein TDP-43 can aggregate in motor neurons. Recently, numerous studies have highlighted the ability of aggregates to spread from neuron to neuron in a prion-like fashion. These studies have typically focused on the use of neuron-like cell lines or neurons that are not normally affected by the specific aggregated protein being studied. Here, we have investigated the uptake of pre-formed SOD1 aggregates by cultures containing pluripotent stem cell-derived human motor neurons. We found that all cells take up aggregates by a process resembling fluid-phase endocytosis, just as found in earlier studies. However, motor neurons, despite taking up smaller amounts of SOD1, were much more vulnerable to the accumulating aggregates. Thus, the propagation of disease pathology depends less on selective uptake than on selective response to intracellular aggregates. We further demonstrate that anti-SOD1 antibodies, being considered as ALS therapeutics, can act by blocking the uptake of SOD1, but also by blocking the toxic effects of intracellular SOD1. This work demonstrates the importance of using disease relevant cells even in studying phenomena such as aggregate propagation.

DOI10.1038/s41598-018-34759-z
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30401824?dopt=Abstract

Alternate JournalSci Rep
PubMed ID30401824
PubMed Central IDPMC6219543