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Travels with tau prions
1Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Abstract:
Tau was originally identified as a microtubule associated protein, and subsequently recognized to constitute the fibrillar assemblies found in Alzheimer disease and related neurodegenerative tauopathies. Point mutations in the microtubule associated protein tau (MAPT) gene cause dominantly inherited tauopathies, and most predispose it to aggregate. This indicates tau aggregation underlies pathogenesis of tauopathies. Our work has suggested that tau functions as a prion, forming unique intracellular pathological assemblies that subsequently move to other cells, inducing further aggregation that underlies disease progression. Remarkably, in simple cells tau forms stably propagating aggregates of distinct conformation, termed strains. Each strain induces a unique and, in some cases, transmissible, neuropathological phenotype upon inoculation into a mouse model. After binding heparan sulfate proteoglycans on the plasma membrane, tau assemblies enter cells via macropinocytosis. From within a vesicle, if not trafficked to the endolysosomal system, tau subsequently enters the cytoplasm, where it becomes a template for its own replication, apparently after processing by valosin containing protein. The smallest seed unit is a stable monomer, which suggests that initial folding events in tau presage subsequent pathological aggregation. The study of tau prions has raised important questions about basic cell biological processes that underlie their replication and propagation, with implications for therapy of tauopathies.
Insights
Tau protein aggregates function as prions, driving neurodegenerative tauopathies. These distinct tau strains propagate between cells, causing unique disease phenotypes and offering therapeutic targets.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Tau protein, identified as a microtubule-associated protein, forms pathological aggregates in Alzheimer disease and related tauopathies.
- Mutations in the MAPT gene linked to inherited tauopathies suggest tau aggregation is central to disease pathogenesis.
- Recent findings propose tau functions as a prion, forming self-propagating intracellular assemblies.
Purpose of the Study:
- To investigate the prion-like behavior of tau protein.
- To characterize the formation, propagation, and cellular entry mechanisms of tau aggregates (strains).
- To explore the implications of tau prion biology for understanding and treating tauopathies.
Main Methods:
- Utilizing simple cell culture systems to study tau aggregate formation and propagation.
- Employing mouse models to assess the neuropathological phenotypes induced by different tau strains.
- Investigating cellular uptake mechanisms, including heparan sulfate proteoglycan binding and macropinocytosis.
- Examining the role of valosin-containing protein in tau replication within the cytoplasm.
Main Results:
- Tau forms distinct, stably propagating aggregate conformations (strains) in simple cells.
- Each tau strain induces unique and transmissible neuropathological phenotypes in mice.
- Tau assemblies enter cells via macropinocytosis after binding to cell surface proteoglycans.
- Cytoplasmic entry and processing by valosin-containing protein are crucial for tau replication.
- Stable monomers represent the smallest seeding unit, indicating early folding events are critical.
Conclusions:
- Tau protein exhibits prion-like characteristics, with distinct strains driving tauopathy pathogenesis.
- Understanding tau prion replication and propagation offers insights into neurodegenerative disease mechanisms.
- Targeting tau prion formation and spread presents a potential therapeutic strategy for tauopathies.
