Figure 1

Hierarchy of nucleolar stress-induced neuroprotection. RNA polymerase I (RNA pol I) is critical for the synthesis of ribosomal RNA (rRNA) and ribosomes, and is regulated by the transcription factor TIF-IA. A variety of protein kinases activated in response to mitogenic signals, growth stimuli, and cellular energy status or in response to oxidative or endoplasmic reticulum stress regulate TIF-IA at distinct serine residues. In HD, the action of nucleolin, which is required for RNA pol I-mediated transcription, is interfered with by expanded CAG RNA molecules and leads to CpG hypermethylation of upstream control elements in the RNA pol I promoter and a reduction in rRNA transcription. Under normal conditions the E3 ubiquitin ligase MDM2 (in mice; HDM2 in human) and proteasome-dependent degradation keeps the transcription factor p53 at low basal levels. Following nucleolar stress various nucleolar proteins (RNPs) inactivate MDM2, thereby stabilizing and increasing p53 levels. Elevated nuclear p53 levels lead to upregulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), which suppresses the mTOR pathway, which is the major inhibitory signal that shuts off autophagy in the presence of growth factors and abundant nutrients. While p53-dependent induction of PTEN, inhibition of mTOR signaling, and autophagy promote neuronal survival and delay neuronal death, MSNs eventually still succumb to p53-independent apoptosis