MAPT mutations associated with familial tauopathies lead to formation of conformationally distinct oligomers that have cross-seeding ability.

Bhopatkar, Anukool A; Bhatt, Nemil; Haque, Md Anzarul; Xavier, Rhea; Fung, Leiana; Jerez, Cynthia; Kayed, Rakez

Bhopatkar, Anukool A; Bhatt, Nemil; Haque, Md Anzarul; Xavier, Rhea; Fung, Leiana; Jerez, Cynthia; Kayed, Rakez.

Afiliación

Bhopatkar AA; Department of Neurology, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas, USA.
Bhatt N; Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA.
Haque MA; Department of Neurology, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas, USA.
Xavier R; Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA.
Fung L; Department of Neurology, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas, USA.
Jerez C; Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA.
Kayed R; Department of Neurology, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas, USA.

Protein Sci ; 33(9): e5099, 2024 Sep.

Article en En | MEDLINE | ID: mdl-39145409

ABSTRACT

ABSTRACT

The microtubule associated protein, tau, is implicated in a multitude of neurodegenerative disorders that are collectively termed as tauopathies. These disorders are characterized by the presence of tau aggregates within the brain of afflicted individuals. Mutations within the MAPT gene that encodes the tau protein form the genetic backdrop for familial forms of tauopathies, such as frontotemporal dementia (FTD), but the molecular consequences of such alterations and their pathological effects are unclear. We sought to investigate the conformational properties of the aggregates of three tau mutants A152T, P301L, and R406W, all implicated within FTD, and compare them to those of the native form (WT-Tau 2N4R). Our immunochemical analysis reveals that mutants and WT tau oligomers exhibit similar affinity for conformation-specific antibodies but have distinct morphology and secondary structure. Additionally, these oligomers possess different dye-binding properties and varying sensitivity to proteolytic processing. These results point to conformational variety among them. We then tested the ability of the mutant oligomers to cross-seed the aggregation of WT tau monomer. Using similar array of experiments, we found that cross-seeding with mutant aggregates leads to the formation of conformationally unique WT oligomers. The results discussed in this paper provide a novel perspective on the structural properties of oligomeric forms of WT tau 2N4R and its mutant, along with shedding some light on their cross-seeding behavior.

Asunto(s)

Tauopatías; Proteínas tau; Proteínas tau/química; Proteínas tau/genética; Proteínas tau/metabolismo; Humanos; Tauopatías/genética; Tauopatías/metabolismo; Mutación; Conformación Proteica; Multimerización de Proteína; Demencia Frontotemporal/genética; Demencia Frontotemporal/metabolismo

Palabras clave

MAPT; conformation; crossseeding; frontotemporal dementia; oligomers; tauopathy

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas tau / Tauopatías Límite: Humans Idioma: En Revista: Protein Sci Asunto de la revista: BIOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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