Proteostasis Deregulation in Neurodegeneration and Its Link with Stress Granules: Focus on the Scaffold and Ribosomal Protein RACK1

Abstract

The role of protein misfolding, deposition, and clearance has been the dominant topic in the last decades of investigation in the field of neurodegeneration. The impairment of protein synthesis, along with RNA metabolism and RNA granules, however, are significantly emerging as novel potential targets for the comprehension of the molecular events leading to neuronal deficits. Indeed, defects in ribosome activity, ribosome stalling, and PQC-all ribosome-related processes required for proteostasis regulation-can contribute to triggering stress conditions and promoting the formation of stress granules (SGs) that could evolve in the formation of pathological granules, usually occurring during neurodegenerating effects. In this review, the interplay between proteostasis, mRNA metabolism, and SGs has been explored in a neurodegenerative context with a focus on Alzheimer's disease (AD), although some defects in these same mechanisms can also be found in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are discussed here. Finally, we highlight the role of the receptor for activated C kinase 1 (RACK1) in these pathologies and note that, besides its well characterized function as a scaffold protein, it has an important role in translation and can associate to stress granules (SGs) determining cell fate in response to diverse stress stimuli.

Keywords: RACK1; RNA; neurodegeneration; proteostasis; stress granules; translation.

Figure 1

The activation of the RQC machinery results in stalled ribosome resolution and degradation of aberrant nascent chains. After scanning the arrested ribosomes, (1) the RQC complex induces the dissociation of the small and large ribosomal subunit, followed by (2) the hydrolysis of the tRNA from the nascent chain, the recycling of the translation machinery and, finally, (3) the degradation through the 28S proteasome of the aberrant nascent chains produced by stalled ribosomes. All these steps are achieved via a fine-tuned regulation of all the molecular players involved, and also thanks to the redundant action of specific proteins, which assures a complete and correct control over the possible errors of the translation process (see text for details).

Figure 2

RQC defects in FTD and ALS and their link with ribosome stalling. (A) The E3 ubiquitin ligase ZNF598 co-translationally regulates the expression of the peptide chain derived from the G₄C₂ repeat expansion in C9orf72 gene, by directing the aberrant peptides to the proteasome system and suppressing the caspase-3-mediated apoptotic pathway. However, the ZNF598R69C mutant observed in pathologic conditions showed a loss of these functions, resulting in translation inhibition. (B) In an ALS context, pathology-correlated mutants R521G and P525L of FUS have a higher cytoplasmic residency and can highly associate with translating ribosomes [42]. Upon mTORC2 inhibition, enhanced FUS association with polyribosomes results in the inhibition of global translation (see text for details).

Figure 3

The unfolded protein response (UPR) and the integrated stress response (ISR). The accumulation of misfolded proteins in the ER leads to ER stress, which triggers intracellular stress sensors (UPR and/or ISR sensors) that can activate stress response pathways to maintain ER homeostasis. However, an excessive unresolved or chronic ER stress can trigger apoptosis responses leading to a different cell fate. The UPR sensors (PERK, IRE1α and ATF6) reside in the ER membrane, while ISR sensors (i.e., PKR, GCN2 and HRI) are cytoplasmic kinases that respond to different stressors than those of the UPR. The UPR and ISR pathways converge at the PERK sensor which, after its dimerization, halts global translation by phosphorylating eIF2α on Ser51. The IRE1α features a cytoplasmic kinase domain and RNase domain; upon dimerization and auto-phosphorylation, IRE1α induces its kinase and endoribonuclease activities, leading to unconventional splicing of X-box-binding protein-1 (XBP1) mRNA [55]. In this regard, RACK1 (receptor for activated C kinase 1) has been reported to activate IRE1α-XBP1 signaling pathway and induce neuroprotection in rat models [56], and the IRE1α-RACK1 axis has been shown to orchestrate cytoprotective responses after ER stress [57]. The ATF6 has a cytoplasmic domain which, upon ER stress, is processed in the Golgi apparatus, and an ATF6 fragment is released in the cytoplasm. After its activation, the UPR pathway induces central transcription factors ATF6, XBP1, and ATF4 that are redirected to the nucleus to mediate the expression of UPR downstream targets [55].

Figure 4

Role of RACK1 in acute and chronic SGs. Together with TIA1 (in violet), PABP (in yellow), and other SG-related RBPs (in dark blue), RACK1 (in green) has been recognised as a ribosomal protein recruited in SG formation. While included within acute SGs produced after type 1 stress promoting cell survival, RACK1 is excluded in chronic SGs after type 2 stress and remains in the cytoplasm, where it can activate the SAPK cascade, leading to JNK and p38 MAPK activation, which results in cell death (see text for details).

Figure 5

Proposed model of RACK1 ribosome- and translation-related roles in healthy aging and neurodegeneration, and its impact on SG-correlated functions. Here, RACK1 levels are reduced in AD patients compared to age-matched healthy controls [99,100] while its ribosome residency and stoichiometry are not altered during healthy aging [167]. Therefore, while RACK1 can contribute to the maintenance of proteostasis with its ribosomal and extra-ribosomal functions discussed here, its reduced levels in a pathological context can contribute to worsening the underlying proteostasis dysregulation observed in different neurodegenerative diseases.