GSE98288
Progressive  motor  neuron  pathology  and  the  role  of  astrocytes  in  a  human  stem  cell model of VCP-related ALS
Motor   neurons (MNs)   and   astrocytes   (ACs) are   implicated   in   the   pathogenesis   of amyotrophic  lateral  sclerosis  (ALS),  but  their  interaction  and  the  sequence  of  molecular events leading to MN death remain unresolved. Herewe optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (>85%) functional populations of  spinal  cord  MNs  and  ACs.  We  identifysignificantlyincreased  cytoplasmic  TDP-43  and  ER stress as  primary  pathogenic  events in patient-specific  valosin-containing  protein  (VCP)-mutant MNs, with  secondary  mitochondrial  dysfunction  and  oxidative  stress.  Cumulatively these  cellular  stresses  result  in  synaptic  pathology  and  cell death  in  VCP-mutant  MNs. We additionallyidentify  a  cell-autonomous VCP-mutant  AC  survival  phenotype, which   is   not attributable  to  the  same  molecular  pathology  occurring in VCP-mutant MNs. Finally, through iterative  co-culture  experiments,  we  uncover  non-cell-autonomous  effects  of  VCP-mutant ACs  on  both  control  and  mutant  MNs.  This  work  elucidates  molecular  events  and  cellular interplay thatcould guide future therapeutic strategies in ALS. Overall design: Bulk RNA-seq at different timepoints throughout a 35-day differentiation protocol that converted iPSC cells to highly enriched motor neurons.