Pathological stress granules in Alzheimer's disease

Abstract

A feature of neurodegenerative disease is the accumulation of insoluble protein aggregates in the brain. In some conditions, including Amyotrophic Lateral Sclerosis and Frontotemporal lobar degeneration, the primary aggregating entities are RNA binding proteins. Through regulated prion-like assembly, RNA binding proteins serve many functions in RNA metabolism that are essential for the healthy maintenance of cells of the central nervous system. Those RNA binding proteins that are the core nucleating factors of stress granules (SGs), including TIA-1, TIAR, TTP and G3BP1, are also found in the pathological lesions of other neurological conditions, such as Alzheimer's disease, where the hallmark aggregating protein is not an RNA binding protein. This discovery suggests that the regulated cellular pathway, which utilizes assembly of RNA binding proteins to package and silence mRNAs during stress, may be integral in the aberrant pathological protein aggregation that occurs in numerous neurodegenerative conditions.

Keywords: Alzheimer’s disease; G3BP1; Pathological stress granules; TIA-1; Tau.

Figure 1. Development of pathological stress granules

RNA binding proteins facilitate many aspects of RNA metabolism including both nuclear and cytoplasmic functions in mRNA splicing, maturation and cellular localization. Under stress conditions, responsive kinases phosphorylate eIF2α leading to the disassembly of the polysome and the induction of SG formation. SGs are nucleated through the binding of core RBPs to mRNA and their self-assembly through the association of prion-related domains. Maturation of SGs follows with the recruitment of secondary RBPs. In disease, prolonged stress, mutations that favor the pro-aggregation state or the inability to recover and disassemble the RBPs leads to the deposition of abundant, large pathological stress granules.

Figure 2. TIA-1-positive tau pathology

8 month old P301L tau transgenic mice display co-localization of TIA-1 (red; SantaCruz) and tau (green; Tau13) in cortical neurons. Nuclei counterstained with DAPI.