Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability
Bilada Bilican, Andrea Serio, Sami J. Barmada, Agnes Lumi Nishimura, Gareth J. Sullivan, Monica Carrasco, Hemali P. Phatnani, Clare A. Puddifoot, David Story, Judy Fletcher, In-Hyun Park, Brad A. Friedman, George Q. Daley, David J. A. Wyllie, Giles E. Hardingham, Ian Wilmut, Steven Finkbeiner, Tom Maniatis, Christopher E. Shaw, Siddharthan Chandran
PNAS, Volume 109, Issue 15, 5803-5808, 10 April 2012
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative conditions in which neurons degenerate causing muscle atrophy and weakness in ALS, or behavioural changes and language deficits in FTD. At the moment there is no cure for these conditions and the average life expectancy is around 3-5 years.
In 2006 it was discovered that in 90% of ALS and 60% of FTD there is an accumulation of clusters of proteins called TDP-43 in the brain cells. The cell death seen in these diseases may be due to the clustered TDP-43 being unable to carry out its essential functions or alternatively; other important proteins may be drawn into the clusters and prevented from functioning.
Our main focus is to study cells called induced pluripotent stem cells (iPSCs) derived from patients with ALS. These iPSCs are derived from adult skin cells in which four early stem cell genes were injected (figure 1). iPSCs can be directed into any type of cells in the body, including cortical and motor neurons. Recently we generated iPSCs from patients with mutations in three proteins related to ALS, including TDP-43, FUS and the new gene c9orf72. The TDP-43 iPSC lines recapitulated key pathological features of ALS and FTD patients with increased TDP-43 mislocalisation, formation of insoluble protein clumps and increased cell death in motor neurons.
The generation of iPSCs from patients with ALS is a remarkable way to understand the ALS disease mechanism and the use of these cells may provide the basis to screen compounds to find a therapeutic agent for ALS.
Summary contributed by an author of the paper, Agnes Nishimura.