Altered ribostasis: RNA-protein granules in degenerative disorders - PubMed (original) (raw)

Review

Altered ribostasis: RNA-protein granules in degenerative disorders

Mani Ramaswami et al. Cell. 2013.

Abstract

The molecular processes that contribute to degenerative diseases are not well understood. Recent observations suggest that some degenerative diseases are promoted by the accumulation of nuclear or cytoplasmic RNA-protein (RNP) aggregates, which can be related to endogenous RNP granules. RNP aggregates arise commonly in degenerative diseases because RNA-binding proteins commonly self-assemble, in part through prion-like domains, which can form self-propagating amyloids. RNP aggregates may be toxic due to multiple perturbations of posttranscriptional control, thereby disrupting the normal "ribostasis" of the cell. This suggests that understanding and modulating RNP assembly or clearance may be effective approaches to developing therapies for these diseases.

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Figures

Figure 1. mRNP remodeling and aggregation in the life cycle of an mRNA

Transcribed RNAs form nuclear mRNPs. RNA-binding proteins associated with mRNA are transported to the cytosol, where they determine cytoplasmic localization, and translational competence of the mRNA. mRNAs begin to assemble translation complexes and then this process is stalled, the mRNPs accumulate as stress granules. mRNPs within stress granules can return to translation initiation and enter polysomes, or be targeted for autophagy. Following translation, mRNAs can exit translation and assemble a translationally repressed mRNP that can either be degraded or assemble into P-bodies. mRNAs within P-bodies can be subject to decapping and 5′ to 3′ degradation, or can exchange P-body components for stress granule components to re-enter translation. Stress granules are proposed to undergo pathological transitions wherein loose assemblies of prion-like domains can form irreversible β-amyloid structures.

Figure 2. Normal Stress granule dynamics and possible evolution of pathogenic inclusions

Cytoplasmic RNP granules such as stress granules and P-bodies assemble due to the presence of prion-like polymerization domains on many RNA binding proteins. In the normal metabolism of cytoplasmic mRNPs these granules reversibly assemble and disassemble, or persistent stress granules may be cleared by autophagy, controlling the content of the translatable pool of mRNAs. We suggest that stable amyloid assemblies may be formed stochastically from normal stress granules and, further, that mutations affecting prion-like domains, or an increased number or persistence of stress granules, increases the probability of this transition. Over time these stable, persistent mRNP assemblies could evolve into the pathological inclusions characteristic of disease and impair ribostasis by sequestration of RNAs or RNA-binding proteins, or by altering signaling pathways.

Figure 3. Three models to account for the special sensitivity of neurons to altered ribostasis caused by enhanced levels of mRNA aggregation

A. Neurons are long-lived cell and therefore accumulate more damage over their lifetimes. In addition, because they are not efficiently replaced by stem cells, neuronal loss is more consequential that the death of a non-neuronal cell like a fibroblast. B. Neurons have higher levels of translationally repressed mRNAs than other cells, particularly in their dendrites and axons. They may therefore be more easily tripped into a pathological state: either by being more responsive to aggregation-inducing conditions, or by being more sensitive to altered RNA regulation. C. The connectivity of neurons results in: (a) enhanced spread of mRNP aggregation from a triggering neuron to a synaptically connected one; or (b) a neuron being particularly susceptible to cell death, when it has lost a synaptic partner on which in may depend for survival signals.

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Altered ribostasis: RNA-protein granules in degenerative disorders - PubMed (original) (raw)