Modeling ALS and other neurological diseases with stem cells.
Guo-Li Ming, Oliver Bru ̈stle, Alysson Muotri, Lorenz Studer, Marius Wernig, and Kimberly M. Christian. 2011. Cellular Reprogramming: Recent Advances in Modeling Neurological Diseases. The Journal of Neuroscience, 31(45):16070 –16075.
Miguel Mitne-Neto1,2, Marcela Machado-Costa3, Maria C.N. Marchetto4, Mario H. Bengtson5, Claudio A. Joazeiro5, Hiroshi Tsuda6, Hugo J. Bellen6, Helga C.A. Silva3, Acary S.B. Oliveira3, Monize Lazar2, Alysson R. Muotri1,∗ and Mayana Zatz. 2011. Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients. Human Molecular Genetics, Vol. 20, No. 18. 3642–3652.
Question 1: About Dr. Alysson Muotri
Dr. Muotri can you please tell us a bit about yourself, your career path over the years and how you began modeling neurological diseases with stem cells?
Question 2: Environmental factors in disorders
On page 16071 of the article Cell Reprogramming: Recent Advances… it is mentioned that “…most disorders show a heritable degree of risk associated with multiple genetic loci, and this risk can be further modulated by epigenetic regulation and environmental factors”- Could you please explain what these other environmental factors are and how they increase or decrease the risk of a disorder?
Question 3: Obstacles in modeling disease
What do you see as the main obstacle in modeling neurological diseases? Since neurons are known to be so malleable and relatively “easy” to induce pluripotency in, is the main issue just epigenetic memory? Or is it extrapolating these monogenic and specific disease models to wider spectrum disorders?
Question 4: iPSC vs animal models
With the advent of greater power to create iPSCs and manipulate hESC to act as disease models, why should the scientific community work to develop more mice (or other) animal models for disease? In a world with limited funding for scientific research, what kind of efforts do you believe will help us more for disease modeling and should be prioritize? Do you think iPSC modeling will eventually completely replace animal models?
Question 5: Modeling diseases with ES vs iPSCs
What do you think are better cells to use, ES or iPS to model human diseases that have no current cure, such as amyotoriphic lateral sclerosis (ALS) or progeria? Why? which one is more reliable for now and the future (such as which one will be more readily/easily available)?
Question 6: Systems controlling VAPB
In the paper “Down regulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients”, you state that both the control and ALS8 fibroblasts show reduced VAPB levels after MG132 treatment, suggesting that protein regulatory systems other then the proteosomes are acting over VAPB pathway. What other systems do think would control VAPB? Have these systems been discovered?
Question 7: What processes are being used to expedite cell maturation for disease modeling
Although the identification and study of neurodegenerative disorders are commonly done with the use of abnormal proteins, in your opinion, how do you think young neuronal cells for modeling late-onset disorders may limit our understanding on the disease and if any, what processes are scientists using to expedite the cell maturation process to better model disease?
Question 8: Challenges for disease modeling in varied disorders
Due to the great variation among Autism Spectrum Disorders, do you encounter any types of specific challenges when modeling these diseases? Do you think it will ever be possible to have one type of iPSC that could be used to model the majority, if not all, of these diseases?
Question 9: ASD mechanisms and SC modeling
In a simplified fashion, would you be so kind as to describe what the general mechanisms that underlie Autism are? Then in what way do you see these mechanisms being mimicked or represented by stem cell modeling?
Question 10: Most pressing questions in the field of modeling human diseases with stem cells
Currently in your opinion what are the most pressing unanswered questions in your field of modeling human diseases with stem cells? What is your lab attempting to do to address these questions?