Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients

Meng Lu Liu, Tong Zang, Chun Li Zhang

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Here, we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs) exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs) with skeletal muscles. Importantly, hiMNs converted from ALS patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification. Liu et al. demonstrate that adult human fibroblasts can be efficiently and directly reprogrammed into highly pure spinal motor neurons (hiMNs). These neurons exhibit mature electrophysiology, form neuromuscular junctions, and control muscle activity. Interestingly, hiMNs from ALS fibroblasts show physiological deficits, which can be ameliorated by a small chemical compound.

Original languageEnglish (US)
Pages (from-to)115-128
Number of pages14
JournalCell Reports
Volume14
Issue number1
DOIs
StatePublished - Jan 5 2016

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Keywords

  • ALS disease
  • Direct reprogramming
  • Kenpaullone
  • Motor neuron
  • NEUROG2
  • Small molecules

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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