A major limitation in understanding the mechanisms of neurodegeneration has been the lack of relevant model systems. The use of appropriate experimental models is especially relevant when testing novel therapeutic approaches. To that end, we utilize patient-specific human neurons derived from iPS (1-3). For Parkinson’s disease, we now have the ability to generate sufficient quantities of relatively pure populations of midbrain dopaminergic neurons that are maintained for extended periods of time in order to model age-dependent alterations and therapeutic strategies. 

Induced Pluripotent Stem Cell (iPS)-derived neurons allow for:

• Assessment of lysosomal function, activities of lysosomal enzymes, lipid profiles, levels of aggregation-prone proteins such as α-synuclein, Tau, Aβ and other specific readouts.
• Age-dependent changes in these readouts.
• Comparison of midbrain dopamine neurons (primarily affected in PD) with non-midbrain dopamine neurons to assess preferential vulnerability of midbrain neurons.
• Differentiating between the genetic and non-genetic factors that contribute to neurodegeneration in human neurons.
• Developing a bank of skin fibroblasts from patients with LSDs and adult onset neurodegenerative diseases for differentiations into neurons as part of future studies.

Referenced Publications

1. Seibler, P., Graziotto,J., Jeong, H., Simunovic F., Klein, C. and Krainc, D. Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 iPS cells. J. Neurosci. 2011 Apr 20;31(16):5970-6. PMID: 21508222  
2. Cooper, O.  Seo H., Andrabi, S., Guardia-Laguarta, C., Graziotto, J., Sundberg, M., McLean, J.R, Carrillo-Reid, L., Osborn, T., Hargus, G., Deleidi, M., Lawson, T., Bogetofte, H., Perez-Torres, E., Clark, L., Moskowitz, C., Mazzulli, J.R., Chen, L., Volpicelli-Daley, L., Romero, N., Jiang, H., Uitti, R.J, Huang, Z., Opala, G., Scarffe, L., Dawson, V.L., Klein, C., Feng, J., Ross, O.R., Trojanowski, J.Q., Lee, V. M.-Y., Marder, K., Surmeier, D.J., Wszolek, Z., Przedborski, S., Krainc, D., Dawson, T.M., Isacson, O. Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease. Science Translational Medicine. 2012 Jul 4;4(141):141ra90. PMID: 22764206 
3. Kriks, S., Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L, Auyeung G, Antonacci C, Buch A, Yang L, Beal MF, Surmeier DJ, Kordower JH, Tabar V, Studer L. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature, 480, 547-551, (2011). PMID: 22056989