Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons
作者： Disi An , Ryosuke Fujiki , Dylan E Iannitelli , John W Smerdon , Shuvadeep Maity
DOI: 10.7554/ELIFE.44423
关键词: Cellular differentiation 、 SOD1 、 Neurodegeneration 、 Stem cell 、 Biology 、 Amyotrophic lateral sclerosis 、 Embryonic stem cell 、 Proteome 、 Cell biology 、 Proteasome
摘要: In amyotrophic lateral sclerosis (ALS) spinal motor neurons (SpMN) progressively degenerate while a subset of cranial (CrMN) are spared until late stages the disease. Using rapid and efficient protocol to differentiate mouse embryonic stem cells (ESC) SpMNs CrMNs, we now report that ESC-derived CrMNs accumulate less human (h)SOD1 insoluble p62 than over time. have higher proteasome activity degrade misfolded proteins intrinsically more resistant chemically-induced proteostatic stress SpMNs. Chemical genetic activation rescues SpMN sensitivity stress. agreement, hSOD1 G93A model reveals ALS-resistant p62-containing inclusions Primary-derived also Thus, an ESC-based platform has identified superior capacity maintain healthy proteome as possible mechanism resist ALS-induced neurodegeneration.
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