Jul
09

In a Bind: RNP Granule Sequestration of RNA-Binding Proteins

Happy July! In cell-ebration of the 4th, I have begun to push my CellDesigner model along, zeroing in ribonucleoprotein (RNP) granules. RNP granules are a class of membrane-less organelles (see last post) that contain RNA-binding proteins (RBPs), RNA, etc., and their dysfunction is implicated in ALS-FTD pathology. RBPs, as previously noted, are prevalent in the problems of ALS-FTD mechanisms, so their appearance in RNP granules may furnish a critical link.

Several important cell components fall into the category of RNP granules, including stress granules, processing bodies (P-bodies), and RNP transport granules. However, the different role each of the RNP granules plays in ALS-FTD pathology remains unclear. While the field has thus far focused most heavily on stress granules (which form to inhibit protein production in response to cellular stress), a few compelling articles have urged me to consider the contribution of other cytoplasmic RNP granules as well.

Particularly of note, the RNP transport granules offer a brain cell-specific mechanism that may contribute to the development and/or progression of ALS-FTD. RNP transport granules move protein machinery to the brain cell’s (sometimes far-reaching) extensions called the axons and dendrites to allow for localized protein control. Axons and dendrites are key players in synaptic transmission, the primary form of neuronal communication, which is critical for movement, perception, memory, and many, many other human functions. Thus, the availability of proteins – the workers of the cells – in axons and dendrites may be a critical question of neurodegeneration and ALS-FTD pathology.

This graphic description from Ling 2018 exhibits the various states of RNA-binding proteins, including their role in different RNP granules.

This graphic description from Ling 2018 exhibits the various states of RNA-binding proteins, including their role in different RNP granules.

My CellDesigner model examines the consequences of (hopefully) both stress granules and RNP transport granules (if time allows, I may include P-bodies; however, these granules do not appear to contain as many proteins implicated in ALS-FTD). Specifically, the model will produce another vantage point of RBP dysfunction from the perspective of sequestration within RNP granules. By modeling RNP granules and the subsequent RNA metabolism processes, I hope to gauge the time course and relative effects of both stress granules and RNP transport granules on related cell processes that are dysregulated in the disease state.

Ling, Shuo-Chien. “Synaptic Paths to Neurodegeneration: The Emerging Role of TDP-43 and FUS in Synaptic Functions.” Neural Plasticity (2018): 1-13. https://doi.org/10.1155/2018/8413496.

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