Physiological protein aggregation run amuck: stress granules and the genesis of neurodegenerative disease

Abstract

Recent advances in neurodegenerative diseases point to novel mechanisms of protein aggregation. RNA binding proteins are abundant in the nucleus, where they carry out processes such as RNA splicing. Neurons also express RNA binding proteins in the cytoplasm and processes to enable functions such as mRNA transport and local protein synthesis. The biology of RNA binding proteins turns out to have important features that appear to promote the pathophysiology of amyotrophic lateral sclerosis and might contribute to other neurodegenerative disease. RNA binding proteins consolidate transcripts to form complexes, termed RNA granules, through a process of physiological aggregation mediated by glycine rich domains that exhibit low protein complexity and in some cases share homology to similar domains in known prion proteins. Under conditions of cell stress these RNA granules expand, leading to form stress granules, which function in part to sequester specialized transcript and promote translation of protective proteins. Studies in humans show that pathological aggregates occurring in ALS, Alzheimer's disease, and other dementias co-localize with stress granules. One increasingly appealing hypothesis is that mutations in RNA binding proteins or prolonged periods of stress cause formation of very stable, pathological stress granules. The consolidation of RNA binding proteins away from the nucleus and neuronal arbors into pathological stress granules might impair the normal physiological activities of these RNA binding proteins causing the neurodegeneration associated with these diseases. Conversely, therapeutic strategies focusing on reducing formation of pathological stress granules might be neuroprotective.

Figure 1

Pathological stress granule formation in neurodegenerative disease. RNA binding proteins carry out many critical cellular functions under basal conditions. A) In the nucleus they regulate RNA splicing and contribute to RNA polymerase elongation by providing helicase activity and position marking. B) In the cytoplasm, they regulate RNA translation and transport transcripts. C) Under stressful conditions, RNA binding proteins translocate to the cytoplasm, where they transiently sequester unnecessary transcripts in stress granules. D) Mutations that enhance aggregation of RNA binding proteins and possibly chronic stress and disease lead to formation of pathological stress granules. Stable, pathological stress granules might cause or exacerbate disease by sequestering RNA binding proteins away from their principle site of action.