![]() While low sequence complexity imparts functional benefits to these proteins, it often proves difficult to study the full-length structure of RBPs. Many of these proteins are conserved from yeast to mammals and contain regions of low complexity ( Hughes et al., 2021). RNA-binding proteins are a class of proteins that interact with RNA and largely function in transcriptional and translational regulation. The significance of these overlapping proteinopathies is not well-characterized, but the RBPs involved share many structural and functional similarities, which will be discussed in the following sections. Other RBPs implicated in these diseases include heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) amongst the FET protein family members (FUS, EWSR1 and TAF15) and others however, we will focus broadly on the roles of TDP-43 and FUS phase separation in physiological and pathological neuronal states. Proteinopathies implicated in both conditions overlap, including TDP-43 and FUS aggregation in the respective neuronal populations ( Ling et al., 2013). RNA-Binding Proteins Implicated in ALS and FTDĪLS is a fatal motor neuron disease that affects both upper and lower motor neurons and leads to their eventual degeneration whereas FTD is another neurodegenerative disease that affects frontal and temporal cortex. Their propensity to undergo LLPS has been well-characterized and they serve as model proteins to study the dynamics of protein phase separation in relation to neurodegenerative diseases. This review will focus on two specific RNA-binding proteins implicated in ALS and FTD pathology: TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS). Overwhelmingly, proteins involved in this phenomenon are RNA-binding proteins (RBPs) and many are implicated in ALS and FTD. In neurons, RNA and protein foci have been reported in various settings including DNA damage repair, local mRNA translation, and neuronal stress response. It is now understood that LLPS is a universal mechanism of condensing proteins and/or RNAs into liquid-like foci for numerous functions. Within the past decade, there has been an exponential rise in studies investigating the role of liquid-liquid phase separation (LLPS) in neurobiology and its pathological consequences in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We discuss possible mechanisms for TDP-43 and FUS aberrant phase transition and aggregation while reviewing the methods that are currently being explored as potential therapeutic strategies to mitigate aberrant phase transition and aggregation of TDP-43 and FUS. Therefore, restoration of functional protein phase of TDP-43 and FUS could be beneficial for neuronal cells. Aberrant phase transition of TDP-43 and FUS leads to protein aggregation and disrupts their regular cell function. We also review evidences that connect the phase separation property of TDP-43 and FUS to their functional roles in cells. In this article, we review the factors that mediate and regulate phase separation of TDP-43 and FUS. They have similar domain structures that provide multivalent interactions driving their phase separation in vitro and in the cellular environment. TDP-43 and FUS are two such RNA-binding proteins that mislocalize and aggregate in patients of ALS and FTD. However, aberrant phase transition of these proteins leads to the formation of insoluble protein aggregates, which are pathological hallmarks of neurodegenerative diseases including ALS and FTD. Liquid-liquid phase separation of RNA-binding proteins mediates the formation of numerous membraneless organelles with essential cellular function. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, United States.
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