TRANSLATIONAL IMPACT
Clinical issue

Amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease) is a disease of fatal motor nerve degeneration, resulting in hallmark symptoms such as progressive muscle weakness, fatigue, and difficulties with speaking, swallowing and breathing. Animal models of inherited ALS have been used in the last decade to test new medications, although the translation of animal work to human studies has been slow. Recently developed methods of generating specific neural cell types from human embryonic stem cells (hESCs) have opened the door to modeling inherited ALS in the cell culture dish using human motor neurons. Stem cells can now be manipulated to express mutant genes linked to ALS. Prior to this work, it has been extremely difficult to introduce and express genes in differentiating stem cells with reliability and consistency. Here, the authors have modified previously published stem cell differentiation protocols to express human mutant SOD1 genes linked to ALS.

Results

The authors describe the optimal transfection time point and cell density for introducing various human SOD1 mutations into hESC-derived cells during their differentiation into motor nerve cells. Nerve cells expressed the SOD1 mutations consistently over several weeks and exhibited hallmark characteristics of motor nerve cells. Compared with wild-type controls, cells expressing mutant SOD1 exhibited motor nerve abnormalities that are typical for ALS, such as reduced life span and reduced cell process length.

Implications and future directions

Progress in understanding human neurodegenerative disease is hampered by the complexity and uniqueness of the human nervous system. This work not only contributes hESCs as a new tool to recapitulate ALS disease, but such cells can also be potentially used within other animal models. The work also highlights the potential of expressing disease-specific gene mutations in embryonic stem cell-derived nerve cells without silencing the introduced genes, which might have implications for a number of other neurodegenerative disorders.