Identification of molecular signatures defines the differential proteostasis response in induced spinal and cranial motor neurons

Ana Paula Zen Petisco Fiore, Shuvadeep Maity, Lauren Jeffery, Disi An, Justin Rendleman, Dylan Iannitelli, Hyungwon Choi, Esteban Mazzoni, Christine Vogel

Research output: Contribution to journalArticlepeer-review

Abstract

Amyotrophic lateral sclerosis damages proteostasis, affecting spinal and upper motor neurons earlier than a subset of cranial motor neurons. To aid disease understanding, we exposed induced cranial and spinal motor neurons (iCrMNs and iSpMNs) to proteotoxic stress, under which iCrMNs showed superior survival, quantifying the transcriptome and proteome for >8,200 genes at 0, 12, and 36 h. Two-thirds of the proteome showed cell-type differences. iSpMN-enriched proteins related to DNA/RNA metabolism, and iCrMN-enriched proteins acted in the endoplasmic reticulum (ER)/ER chaperone complex, tRNA aminoacylation, mitochondria, and the plasma/synaptic membrane, suggesting that iCrMNs expressed higher levels of proteins supporting proteostasis and neuronal function. When investigating the increased proteasome levels in iCrMNs, we showed that the activity of the 26S proteasome, but not of the 20S proteasome, was higher in iCrMNs than in iSpMNs, even after a stress-induced decrease. We identified Ublcp1 as an iCrMN-specific regulator of the nuclear 26S activity.

Original languageEnglish (US)
Article number113885
JournalCell Reports
Volume43
Issue number3
DOIs
StatePublished - Mar 26 2024

Keywords

  • CP: Cell biology
  • CP: Neuroscience
  • Ublcp1
  • amyotrophic lateral sclerosis
  • motor neurons
  • proteasome
  • unfolded protein response

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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