Dysregulation of RNA Binding Protein Aggregation in Neurodegenerative Disorders - PubMed (original) (raw)

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Dysregulation of RNA Binding Protein Aggregation in Neurodegenerative Disorders

Brandon Maziuk et al. Front Mol Neurosci. 2017.

Abstract

The unique biology of RNA binding proteins is altering our view of the genesis of protein misfolding diseases. These proteins use aggregation of low complexity domains (LCDs) as a means to regulate the localization and utilization of RNA by forming RNA granules, such as stress granules, transport granules and P-bodies. The reliance on reversible aggregation as a mechanism for biological regulation renders this family of proteins highly vulnerable to promoting diseases of protein misfolding. Mutations in RNA binding proteins are associated with many neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). The biology of RNA binding proteins also extends to microtubule associated protein tau. Tau is normally an axonal protein, but in stress it translocates to the somatodendritic arbor where it takes on a new function promoting formation of stress granules. The interaction of tau with stress granules also promotes tau aggregation, accelerating formation of the tau pathology that we associate with diseases such as Alzheimer's disease (AD).

Keywords: RNA Translation; RNA binding proteins; RNA metabolism; stress response; tau aggregation.

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Figures

Figure 1

Figure 1

Liquid-liquid phase separation contributes to RNP granule dynamics and eventual fibrillization. Within the cytosol, RNA binding proteins (RBPs) containing low complexity prion-like domains (LCDs) exist in an unaggregated state. Upon activating signaling cascades, the LCDs mediate weak aggregation through liquid-liquid phase separation, creating a distinct compartment enriched in RBPs, RNA and other associated proteins. Importantly, these ribonucleoprotein granules maintain the ability to exchange material with the cytosol while in this state, which allows them to carry out key mRNA regulating events. However, persistent aggregation over time or other pathological insults can drive these RBPs to further aggregate into compact, stable fibrils. In this model, the fibrillar forms of these granules can no longer exchange material with the surrounding cytosol and effectively trap their components in the granule.

Figure 2

Figure 2

Interaction of Tau and RBP pathologies: (1) RBPs such as TIA1 splice RNA in the nucleus, and shuttle in and out of the nucleus. Although TIA1 is normally predominantly nuclear, Tau slows nuclear/cytoplasmic transport, decreasing anterograde transport less than retrograde transport, overall favoring a cytoplasmic localization of TIA1. (2) Tau binds to the small subunit of ribosomes, and this interaction changes in taupathies such as AD, resulting in stalled translation. Stalled translation initiation complexes containing mRNA and the small ribosomal subunit forms complexes with ribosomal proteins, mRNA, and core SG nucleating RBPs. (3) Small core stress granules forms complexes with additional RBPs including DDX helicases. (4) Tau increases the size of stress granules, and influences the specificity of RBPs included in stress granules. RBPs in complex with Tau and TIA1 include TAF15 and EWSR1. (5) TIA1 mediates interaction of stress granules with insoluble tau aggregates internalized from the cytoplasm (Meier et al., ; Brunello et al., ; Vanderweyde et al., 2016).

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