Promyelocytic leukemia protein (PML) is a regulator of eNSC differentiation, survival and mitochondrial metabolism.

ABSTRACT: OThis study identifies the tumor suppressor PML as a regulator of embryonic neural stem cell (eNSC) homeostasis, highlighting its role in their proliferation, differentiation and metabolism. Loss of the promyelocytic leukemia (PML) protein has been previously linked to abnormal proliferation and diffentiation of embryonic neurons. Here we show that PML ablation inhibits the neuronal and oligodendrocytic lineages but favors the astrocytic pathway. A detailed analysis of the gene expression changes caused by PML loss in E13.5 NSC at both the RNA and protein level identifies several important cell pathways to be deregulated. Of note, PPARg activity, lipid and mitochondrial metabolism are down-regulated. Conversely, the mTOR and protein translation activities were upregulated. Pml-/- eNSC showed increased proliferation compared with the WT due to increased activation of the PI3K/AKT/mTOR pathway. In agreement with increased mTOR we detected reduced autophagic flux in Pml-/- cells and decreased proteasomal activity accompanied with an increase in the formation of intracellular aggregates. Functionally, Pml-/- mitochondria exhibit lower mitochondrial membrane potential, increased levels of ROS and morphological alterations. Mitochondrial defects observed in Pml-/- neural progenitors, might be attributed to reduced expression of PGC1a and impaired PPARγ signaling that can be transcriptionally and functionally restored by the action of a PPAR agonist. In summary, PML deficient NSC share commonalities with cells undergoing aging and/or neurodegeneration. Thus, we identify PML as a factor that supports neuronal survival and protects from neurotoxicity and propose that enforced PML expression may restore a compromised PPARg/PGC1A expression or function and offer therapeutic benefit.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Suspension Culture, Stem Cell

SUBMITTER: Martina Samiotaki  

LAB HEAD: Androniki Kretsovali

PROVIDER: PXD059100 | Pride | 2025-09-29

REPOSITORIES: Pride