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Combating deleterious phase transitions in neurodegenerative disease.

ABSTRACT: Protein aggregation is a hallmark of neurodegenerative diseases. However, the mechanism that induces pathogenic aggregation is not well understood. Recently, it has emerged that several of the pathological proteins found in an aggregated or mislocalized state in neurodegenerative diseases are also able to undergo liquid-liquid phase separation (LLPS) under physiological conditions. Although these phase transitions are likely important for various physiological functions, neurodegenerative disease-related mutations and conditions can alter the LLPS behavior of these proteins, which can elicit toxicity. Therefore, therapeutics that antagonize aberrant LLPS may be able to mitigate toxicity and aggregation that is ubiquitous in neurodegenerative disease. Here, we discuss the mechanisms by which aberrant protein phase transitions may contribute to neurodegenerative disease. We also outline potential therapeutic strategies to counter deleterious phases. State without borders: Membrane-less organelles and liquid-liquid phase transitions edited by Vladimir N Uversky.

SUBMITTER: Darling AL

PROVIDER: S-EPMC7965345 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Combating deleterious phase transitions in neurodegenerative disease.

Darling April L AL Shorter James J

Biochimica et biophysica acta. Molecular cell research 20210205 5

Protein aggregation is a hallmark of neurodegenerative diseases. However, the mechanism that induces pathogenic aggregation is not well understood. Recently, it has emerged that several of the pathological proteins found in an aggregated or mislocalized state in neurodegenerative diseases are also able to undergo liquid-liquid phase separation (LLPS) under physiological conditions. Although these phase transitions are likely important for various physiological functions, neurodegenerative diseas ...[more]

PMID: 33549703

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Project description:Liquid-liquid phase separation results in the formation of dynamic biomolecular condensates, also known as membrane-less organelles, that allow for the assembly of functional compartments and higher order structures within cells. Multivalent, reversible interactions between RNA-binding proteins (RBPs), including FUS, TDP-43, and hnRNPA1, and/or RNA (e.g., RBP-RBP, RBP-RNA, RNA-RNA), result in the formation of ribonucleoprotein (RNP) condensates, which are critical for RNA processing, mRNA transport, stability, stress granule assembly, and translation. Stress granules, neuronal transport granules, and processing bodies are examples of cytoplasmic RNP condensates, while the nucleolus and Cajal bodies are representative nuclear RNP condensates. In neurons, RNP condensates promote long-range mRNA transport and local translation in the dendrites and axon, and are essential for spatiotemporal regulation of gene expression, axonal integrity and synaptic function. Mutations of RBPs and/or pathologic mislocalization and aggregation of RBPs are hallmarks of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease. ALS/FTD-linked mutations of RBPs alter the strength and reversibility of multivalent interactions with other RBPs and RNAs, resulting in aberrant phase transitions. These aberrant RNP condensates have detrimental functional consequences on mRNA stability, localization, and translation, and ultimately lead to compromised axonal integrity and synaptic function in disease. Pathogenic protein aggregation is dependent on various factors, and aberrant dynamically arrested RNP condensates may serve as an initial nucleation step for pathologic aggregate formation. Recent studies have focused on identifying mechanisms by which neurons resolve phase transitioned condensates to prevent the formation of pathogenic inclusions/aggregates. The present review focuses on the phase separation of neurodegenerative disease-linked RBPs, physiological functions of RNP condensates, and the pathologic role of aberrant phase transitions in neurodegenerative disease, particularly ALS/FTD. We also examine cellular mechanisms that contribute to the resolution of aberrant condensates in neurons, and potential therapeutic approaches to resolve aberrantly phase transitioned condensates at a molecular level.

Dataset Information

Combating deleterious phase transitions in neurodegenerative disease.

Publications

Combating deleterious phase transitions in neurodegenerative disease.

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