DISEASE MECHANISM AND MODELS FOR ALS
MetadataShow full item record
Amyothrophic lateral sclerosis (ALS, Lou Gehrig’s disease) is a severe adult-onset neurodegenerative disease, characterized by progressive premature loss of upper and lower motor neurons. Eventually the disease leads to death due to respiratory failure1. ALS is the third most common neurodegenerative disease2 and cause of adult mortality3. It appears to be caused by a complex interaction among genetics and environmental factors2. While approximately 10% of ALS cases are familial, the remaining cases are believed to be sporadic. However, the exact working mechanism underlying the selective motor neuron death in ALS is not resolved yet. Since a wide variety of cellular processes are involved in ALS, a general, systemic principle might underlie it. Recent data provides compelling evidence for a major role of aging in the development of ALS4,5,6,7. This hypothesis was enhanced by the discovery that reduced Insulin/IGF signalling (IIS) correlates with lifespan extension8 and a decreased risk to develop ALS9. Its pathway is not only regulating lifespan, metabolism and stress resistance4, TDP-43 has also showed to be part of it, a well known ALS gene9. TDP-43 is primarily a nuclear protein that participates in common heteromultimeric complexes, which is involved into diverse RNA processes and stress granule formation16,10. Furthermore, TDP-43 is identified as the major component of insoluble cytoplastic inclusions in both sALS as fALS, and associated with the oxidative stress response. It seems likely that this TDP-43 protein mediates longevity through activation of the IIS pathway under stressfull conditions11. Besides the activation of various cellular cascades, there is a vicious circle in which TDP-43 expression becomes upregulated. Interestingly, it has been found that during stress, the threshold for TDP-43 phosphorylation is lowered. This lead to increased proteotoxicity12. This in turn seems to cause and/or to accelerate motor neuron degeneration. However, besides aging, also heavy exercise is in part mediated by the IIS pathway and involved in ALS development13. During heavy exercise, enormous amount of ROS are generated which causes oxidative stress and disturb the epigenetic codes14. Interestingly, age-related changes seemed to be determined by the age of the systemic environment, rather than by the cell-autonomous age15. Therefore, it has been suggested that signals from the systemic environment drive age-related, intrinsic changes, mediated by the IIS pathway. This activates a cascade of events that eventually can lead to ALS pathology. However, current animal models are not suitable to further investigate this postulation. Not only did the obtained results fail when translated to the human situation, also are fundamental genetic and anatomical differences between both species in age-related pathways found16,17. Therefore, new and improved models are needed. In vitro cell based therapies seems to be the first feasible model to investigate the disease mechanism for both sALS and fALS by utilizing induced pluripotent stem cells (iPSCs)18. iPSCs can give us insights into disease mechanisms, drug discovery, cell therapy and a potential new diagnostic method for patients with ALS19,20,21. Furthermore, will this technique enable the identification of a systemic regulation of aging on ALS pathology in patient derived iPSCs.