A neuroprotective phase precedes striatal degeneration upon nucleolar stress

Abstract

The nucleolus is implicated in sensing and responding to cellular stress by stabilizing p53. The pro-apoptotic effect of p53 is associated with several neurodegenerative disorders, including Huntington's disease (HD), which is characterized by the progressive loss of medium spiny neurons (MSNs) in the striatum. Here we show that disruption of nucleolar integrity and function causes nucleolar stress and is an early event in MSNs of R6/2 mice, a transgenic model of HD. Targeted perturbation of nucleolar function in MSNs by conditional knockout of the RNA polymerase I-specific transcription initiation factor IA (TIF-IA) leads to late progressive striatal degeneration, HD-like motor abnormalities and molecular signatures. Significantly, p53 prolongs neuronal survival in TIF-IA-deficient MSNs by transient upregulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor that inhibits mammalian target of rapamycin signaling and induces autophagy. The results emphasize the initial role of nucleolar stress in neurodegeneration and uncover a p53/PTEN-dependent neuroprotective response.

The nucleolus fine-tunes the orchestration of an early neuroprotection response in neurodegeneration

“…13 The role of autophagy in protection against neurodegenerative diseases has been established in animal models, 14 and while autophagy is present in HD and AD brain, 15 neurons in the final stages of their death often display counteracting pro-death factors and pro-survival responses. In this issue, results in the study by Kreiner and co-workers 16 provide further evidence that autophagy has a protective role in the early stages of neurodegeneration [16][17][18] using a model of HD as part of a desperate attempt by the cell to save itself from destruction (see Figure 1). …”

“…The Kreiner et al 16 study highlights that TIF-IA mutant mice can be used to advance and authenticate therapeutic intervention to promote autophagy as a survival mechanism and discover biomarkers associated with this degenerative model. The cellular decisions between autophagy or apoptotic death pathways include potentially variable thresholds for each process, the role of differential post-translational processing of p38, and mutual inhibition or activation of each pathway by the other.…”

Nucleolar Enrichment of Brain Proteins with Critical Roles in Human Neurodevelopment

“…In the nervous system, neither components nor regulators of the ribosomal biogenesis pathway have been systematically investigated with the exception of the Pol1 co-factor TIF1A whose knockdown or knockout blocks rRNA transcription in various neuronal populations (12,13,25,26). Likewise, there is little information on nonribosomal functions of brain cell nucleoli beyond their involvement in the p53 stress response pathway.…”

Understanding Huntington's disease using Machine Learning Approaches

“…Repeat-containing RNA has been demonstrated to associate with nucleolar protein complexes leading to "nucleolar stress", which is thought to trigger cell death through activating the p53 mediated pathway. (Kreiner et al, 2013) This phenomenon has been shown to be relevant for certain degenerative disorders of repeat sequences, including HD (Tsoi et al, 2012), ALS and frontotemporal dementia. (Haeusler et al, 2014) Interestingly, results from our laboratory have recently demonstrated that mHtt toxicity in yeast can be suppressed by several rDNA genes (Chatterjee et al, 2013), most notably by the gene encoding L12p, a member of the L11p subgroup of ribosomal proteins.…”

“…(Maehama et al, 2014) An additional connection between mHtt and chromosome condensation defects exists which is implicated in DNA damage and apoptotic cell death in mammalian cells. (Blank et al, 2006) Abnormal association of repeatcontaining RNA with nucleolar protein complexes is known to cause "nucleolar stress" and activates the p53 pathway to trigger cell death (Kreiner et al, 2013), a process shown to be important for HD. (Tsoi et al, 2012) Thus, while neurons do not undergo mitosis, their death might indeed be triggered by rDNA condensation defects through the same molecular pathways that are used in mitotic DNA repair.…”