Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons
Disi An,
Ryosuke Fujiki,
Dylan E Iannitelli,
John W Smerdon,
Shuvadeep Maity,
Matthew F Rose,
Alon Gelber,
Elizabeth K Wanaselja,
Ilona Yagudayeva,
Joun Y Lee,
Christine Vogel,
Hynek Wichterle,
Elizabeth C Engle,
Esteban Orlando Mazzoni
Affiliations
Disi An
Department of Biology, New York University, New York, United States
Ryosuke Fujiki
Department of Neurology, Boston Children’s Hospital, Boston, United States; FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States; Department of Neurology, Harvard Medical School, Boston, United States; Medical Genetics Training Program, Harvard Medical School, Boston, United States
Department of Biology, New York University, New York, United States; Center for Genomics and Systems Biology, New York University, New York, United States
Department of Neurology, Boston Children’s Hospital, Boston, United States; FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States; Medical Genetics Training Program, Harvard Medical School, Boston, United States; Department of Pathology, Brigham and Women’s Hospital, Boston, United States; Department of Pathology, Boston Children’s Hospital, Boston, United States; Department of Pathology, Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
Alon Gelber
Department of Neurology, Boston Children’s Hospital, Boston, United States; FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States
Elizabeth K Wanaselja
Department of Biology, New York University, New York, United States
Ilona Yagudayeva
Department of Biology, New York University, New York, United States
Joun Y Lee
Department of Neurology, Boston Children’s Hospital, Boston, United States; FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States
Department of Biology, New York University, New York, United States; Center for Genomics and Systems Biology, New York University, New York, United States
Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States
Elizabeth C Engle
Department of Neurology, Boston Children’s Hospital, Boston, United States; FM Kirby Neurobiology Center, Boston Children’s Hospital, Boston, United States; Department of Neurology, Harvard Medical School, Boston, United States; Medical Genetics Training Program, Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United States; Howard Hughes Medical Institute, Chevy Chase, United States; Department of Ophthalmology, Boston Children’s Hospital, Boston, United States; Department of Ophthalmology, Harvard Medical School, Boston, United States
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.
