Disrupting pathologic phase transitions in neurodegeneration
Bryan T. Hurtle, Longxin Xie, Christopher J. Donnelly
Bryan T. Hurtle, Longxin Xie, Christopher J. Donnelly
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Review

Disrupting pathologic phase transitions in neurodegeneration

Abstract

Solid-like protein deposits found in aged and diseased human brains have revealed a relationship between insoluble protein accumulations and the resulting deficits in neurologic function. Clinically diverse neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis, exhibit unique and disease-specific biochemical protein signatures and abnormal protein depositions that often correlate with disease pathogenesis. Recent evidence indicates that many pathologic proteins assemble into liquid-like protein phases through the highly coordinated process of liquid-liquid phase separation. Over the last decade, biomolecular phase transitions have emerged as a fundamental mechanism of cellular organization. Liquid-like condensates organize functionally related biomolecules within the cell, and many neuropathology-associated proteins reside within these dynamic structures. Thus, examining biomolecular phase transitions enhances our understanding of the molecular mechanisms mediating toxicity across diverse neurodegenerative diseases. This Review explores the known mechanisms contributing to aberrant protein phase transitions in neurodegenerative diseases, focusing on tau and TDP-43 proteinopathies and outlining potential therapeutic strategies to regulate these pathologic events.

Authors

Bryan T. Hurtle, Longxin Xie, Christopher J. Donnelly

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Figure 1

Phase transitions of NDD-related proteins.

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Phase transitions of NDD-related proteins. (A) Domain structure and inte...
(A) Domain structure and interaction features of TDP-43 and tau. TDP-43 contains three domains: an N-terminal domain (NTD) including a nuclear localization sequence (NLS); two RNA recognition motifs (RRM1 and RRM2); and a C-terminal domain (CTD) with a short α-helical fold (CR helix) and a glutamine/arginine-rich region (Q/N). Tau contains four domains: the negatively charged NTD and CTD, and the positively charged proline-rich domain (P1–P2) and microtubule-binding domain (MTBD; R1–R4). Six different tau isoforms are generated by alternative splicing containing zero, one, or two NTD inserts and three or four MTBD repeats. The intrinsically disordered regions (IDRs), aggregation-prone steric zippers, and domain-dependent homo/heterotypic biomolecular interactions of TDP-43 and tau are shown accordingly. LLPS, liquid-liquid phase separation. (B) Aberrant protein conformations, toxic polymeric self-assemblies, and solid accumulations of proteins are found across the most common NDDs. TDP-43 and tau are modular, multivalent proteins exhibiting conformational flexibility, allowing diverse monomeric conformations, polymeric assemblies, and liquid-like phase behaviors in normal physiology and pathology. Sequence-specific properties found within distinct protein domains (modular interaction domains, intrinsically disordered regions, and amyloid-forming regions) are influenced by intrinsic (isoforms, mutations, PTMs) and extrinsic factors (molecular interactions, environmental conditions), ultimately regulating phase behavior and unique polymerization pathways. While increased homotypic interactions drive protein self-polymerization and the phase separation of proteins into liquid-like droplets, they are independent processes regulated by overlapping conditions. (C) TDP-43 and tau reside within multicomponent biomolecular condensates and thus are subjected to diverse homo/heterotypic biomolecular interactions, ultimately regulating physiologic and pathologic phase transitions. Biomolecules necessary for condensate assembly (scaffolds) spatially organize and concentrate functionally related biomolecules (clients) through liquid-like phase transitions. A sticker and spacer model has been proposed in which sticker sequences regulate multivalent networking interactions and spacer sequences regulate the solubilities of individual biomolecules and emerging networks.