@article{80e147e2f00e44d9bc7fe4e74e9edc4c,
title = "Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons",
abstract = "In amyotrophic lateral sclerosis (ALS) spinal motor neurons (SpMN) progressively degenerate while a subset of cranial motor neurons (CrMN) are spared until late stages of the disease. Using a rapid and efficient protocol to differentiate mouse embryonic stem cells (ESC) to SpMNs and CrMNs, we now report that ESC-derived CrMNs accumulate less human (h)SOD1 and insoluble p62 than SpMNs over time. ESC-derived CrMNs have higher proteasome activity to degrade misfolded proteins and are intrinsically more resistant to chemically-induced proteostatic stress than SpMNs. Chemical and genetic activation of the proteasome rescues SpMN sensitivity to proteostatic stress. In agreement, the hSOD1 G93A mouse model reveals that ALS-resistant CrMNs accumulate less insoluble hSOD1 and p62-containing inclusions than SpMNs. Primary- derived ALS-resistant CrMNs are also more resistant than SpMNs to proteostatic stress. Thus, an ESC-based platform has identified a superior capacity to maintain a healthy proteome as a possible mechanism to resist ALS-induced neurodegeneration.",
author = "Disi An and Ryosuke Fujiki and Iannitelli, {Dylan E.} and Smerdon, {John W.} and Shuvadeep Maity and Rose, {Matthew F.} and Alon Gelber and Wanaselja, {Elizabeth K.} and Ilona Yagudayeva and Lee, {Joun Y.} and Christine Vogel and Hynek Wichterle and Engle, {Elizabeth C.} and Mazzoni, {Esteban Orlando}",
note = "Funding Information: The authors would like to thank the Mazzoni lab members for constructive comments. We thank SL Pfaff (Salk Institute for Biological Studies, La Jolla, California, USA) for IslMN:GFP reporter mice; Bri-gitte Pettmann (Biogen, Cambridge, MA, USA) for instruction in SpMN dissection techniques; the Dana Farber Cancer Institute Flow Cytometry Facility, the Immunology Division Flow Cytometry Facility of Harvard Medical School, The Joslin Diabetes Center Flow Cytometry Core, Brigham and Women{\textquoteright}s Hospital Flow Cytometry Core, and Boston Children{\textquoteright}s Hospital Flow Cytometry Research Facility for FACS isolation of primary motor neurons; AS Lee, AA Nugent, AP Tenney, MC Whitman, Engle laboratory members, and Project ALS consortium members for technical assistance and thoughtful discussion. We thank Seungkyu Lee for help in collecting single primary motor neurons. We also thank the Regev Lab/Klarman Cell Observatory at the Broad Institute for access to their next generation sequencing equipment. We thank Yi Fu for help in establishing hSOD1 transgenic ESC lines and thank Dr. L Giono for helping with the summary figure. This work was primarily supported by the PROJECT ALS grant A13-0416 to HW, ECE and EOM. Additional support from NYDH grant DOH01-C32243GG-3450000, MODBDF grant #5-FY14-99 and NICHD R01HD079682 to EOM. NIH/NINDS F31 NS 095571 and 103447 to JWS and DEI respectively. DA was partially supported by the NYU Dean{\textquoteright}s Dissertation award. RF was funded by Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad and NIH Training grant in Genetics T32 GM007748. MFR was funded by NIH/NINDS (K08NS099502) and by NIH Training grants in HMS Genetics (NIGMS, T32-GM007748) and BWH Pathology (NHLBI, T32-HL007627). ECE is a Howard Hughes Medical Institute Investigator. CV acknowledges funding by the NIH/NIGMS (R01 GM113237 and 1R35GM127089-01), and the Zegar Family Foundation Fund for Genomics Research at New York University. Funding Information: Project ALS A13-0416 Hynek Wichterle Elizabeth C Engle Esteban Orlando Mazzoni Eunice Kennedy Shriver National Institute of Child Health and Human Development R01HD079682 Esteban Orlando Mazzoni New York State Department of Health DOH01-C32243GG-3450000 Esteban Orlando Mazzoni March of Dimes March Of Dimes Birth Defects Foundation #5- FY14-99 Esteban Orlando Mazzoni National Institute of Neurological Disorders and Stroke F31 NS 095571 John W Smerdon National Institute of Neurological Disorders and Stroke F31 103447 Dylan E Iannitelli New York University Dean{\textquoteright}s Dissertation award Disi An Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad Ryosuke Fujiki National Institutes of Health T32 GM007748 Ryosuke Fujiki National Institute of Neurological Disorders and Stroke Matthew F Rose National Institute of General Medical Sciences T32-GM007748 Matthew F Rose National Heart, Lung, and Blood Institute T32-HL007627) Matthew F Rose Howard Hughes Medical Institute Elizabeth C Engle National Institute of General Medical Sciences R01 GM113237 Christine Vogel National Institute of General Medical Sciences 1R35GM127089-01) Christine Vogel Zegar Family Foundation Fund for Genomics Research at New York University The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Publisher Copyright: {\textcopyright} An et al.",
year = "2019",
month = jun,
doi = "10.7554/eLife.44423",
language = "English (US)",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}