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Sensitive Detection of Proteopathic Seeding Activity with FRET Flow Cytometry
Published on: December 8, 2015
Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights
Kevin H Strang1,2, Cara L Croft1,2, Zachary A Sorrentino1,2
1From the Department of Neuroscience.
Abstract:
The accumulation of aberrantly aggregated MAPT (microtubule-associated protein Tau) defines a spectrum of tauopathies, including Alzheimer's disease. Mutations in the MAPT gene cause frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), characterized by neuronal pathological Tau inclusions in the form of neurofibrillary tangles and Pick bodies and in some cases glial Tau pathology. Increasing evidence points to the importance of prion-like seeding as a mechanism for the pathological spread in tauopathy and other neurodegenerative diseases. Herein, using a cell culture model, we examined a multitude of genetic FTDP-17 Tau variants for their ability to be seeded by exogenous Tau fibrils. Our findings revealed stark differences between FTDP-17 Tau variants in their ability to be seeded, with variants at Pro301 and Ser320 showing robust aggregation with seeding. Similarly, we elucidated the importance of certain Tau protein regions and unique residues, including the role of Pro301 in inhibiting Tau aggregation. We also revealed potential barriers in cross-seeding between three-repeat and four-repeat Tau isoforms. Overall, these differences alluded to potential mechanistic differences between wildtype and FTDP-17 Tau variants, as well as different Tau isoforms, in influencing Tau aggregation. Furthermore, by combining two FTDP-17 Tau variants (either P301L or P301S with S320F), we generated aggressive models of tauopathy that do not require exogenous seeding. These models will allow for rapid screening of potential therapeutics to alleviate Tau aggregation without the need for exogenous Tau fibrils. Together, these studies provide novel insights in the molecular determinants that modulate Tau aggregation.
Insights
Genetic mutations in microtubule-associated protein Tau (MAPT) cause frontotemporal dementia. Certain MAPT variants show differences in aggregation, revealing key regions and residues that influence tauopathy progression and therapeutic development.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Aberrant aggregation of microtubule-associated protein Tau (MAPT) characterizes tauopathies, including Alzheimer's disease.
- Mutations in the MAPT gene lead to frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), marked by pathological Tau inclusions.
- Prion-like seeding is increasingly recognized as a mechanism for the spread of tauopathy and other neurodegenerative diseases.
Purpose of the Study:
- To investigate the prion-like seeding ability of various genetic FTDP-17 MAPT variants in a cell culture model.
- To identify specific MAPT protein regions and residues critical for Tau aggregation and seeding.
- To explore potential cross-seeding barriers between different Tau isoforms.
Main Methods:
- Utilized a cell culture model to examine the seeding capabilities of multiple genetic FTDP-17 MAPT variants.
- Assessed the aggregation propensity of Tau variants when exposed to exogenous Tau fibrils.
- Generated combined FTDP-17 MAPT variant models to create aggressive tauopathy models.
Main Results:
- Demonstrated significant differences in seeding ability among FTDP-17 MAPT variants, with Pro301 and Ser320 variants showing robust aggregation.
- Elucidated the role of specific regions and residues, such as Pro301, in modulating Tau aggregation.
- Identified potential cross-seeding barriers between three-repeat and four-repeat Tau isoforms.
- Developed aggressive tauopathy models by combining specific FTDP-17 MAPT variants (P301L/S with S320F) that do not require exogenous seeding.
Conclusions:
- Found mechanistic differences between wildtype and FTDP-17 MAPT variants, and among different Tau isoforms, in their influence on Tau aggregation.
- Highlighted the importance of specific molecular determinants in modulating Tau aggregation.
- Established aggressive tauopathy models for rapid screening of potential therapeutics targeting Tau aggregation.
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