Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease.

Cooper O, Seo H, Andrabi S, Guardia-Laguarta C, Graziotto J, Sundberg M, McLean JR, Carrillo-Reid L, Xie Z, Osborn T, Hargus G, Deleidi M, Lawson T, Bogetofte H, Perez-Torres E, Clark L, Moskowitz C, Mazzulli J, Chen L, Volpicelli-Daley L, Romero N, Jiang H, Uitti RJ, Huang Z, Opala G, Scarffe LA, Dawson VL, Klein C, Feng J, Ross OA, Trojanowski JQ, Lee VM, Marder K, Surmeier DJ, Wszolek ZK, Przedborski S, Krainc D, Dawson TM, Isacson O. Sci Transl Med. 2012 Jul 4;4(141):141ra90 This was a paper I read that I really thought I was going to like, but once I read through it something seemed to be missing. I thought that there were some experiments that probably should have been done that didn’t get included in the paper, and some things that were in there without a good rationale or explanation. Then again, I could have just missed out on finding their explanations… In this paper, the authors used fibroblasts isolated from people which were found positive for markers of familial Parkinson’s disease. They attempted to test the interaction of familial mutations and different chemical stressors by making the fibroblasts into induced pluripotent stem cells and then differentiating them into neural cells. They assessed the health of the induced dopaminergic neurons by measuring mitochondrial function as the mutations they studied were in PINK1 and LRRK2, two proteins known to be involved in mitochondrial turnover. So what kind of things do I think were missing? Well, one thing that concerned me was that the cultures of differentiated “neural cells” they used included dopaminergic cells along with non-dopaminergic and immature cells in unspecified proportions. All cells were treated the same way (with drugs that did not act specifically on dopaminergic cells), but the observed effects were attributed to the dopaminergic cells. One obvious thing that I would have done was to use a chemical stressor with a good specificity to dopaminergic cells, like MPTP. People have known how MPTP induces parkinsonism by selective dopaminergic neurotoxicity for decades, so why they would leave out something like that is kind of a mystery to me. I don’t want to bash the paper, because I liked the idea and some of the results, but it seems like the experimental design was lacking, or maybe that there were so many groups/authors each doing a part of the study that nobody could really agree on one central thread that they should follow. Given that we’re starting some new studies with a lot of input and help from different people/specialties, the hazard of this kind of thing has been wobbling around in my brain for a while. I’m just hoping that we can manage to keep our eyes on the prize of forming a grand unified theory of RVLM and not get caught with too many fingers in the pie. Also I’m hoping to stop mixing my metaphors. -DH