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Biochemical approaches to assess the impact of post-translational modifications on pathogenic tau conformations using recombinant protein.
Alhadidy, Mohammed M; Kanaan, Nicholas M.
Afiliação
  • Alhadidy MM; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, U.S.A.
  • Kanaan NM; Neuroscience Program, Michigan State University, East Lansing, MI, U.S.A.
Biochem Soc Trans ; 52(1): 301-318, 2024 02 28.
Article em En | MEDLINE | ID: mdl-38348781
ABSTRACT
Tau protein is associated with many neurodegenerative disorders known as tauopathies. Aggregates of tau are thought of as a main contributor to neurodegeneration in these diseases. Increasingly, evidence points to earlier, soluble conformations of abnormally modified monomers and multimeric tau as toxic forms of tau. The biological processes driving tau from physiological species to pathogenic conformations remain poorly understood, but certain avenues are currently under investigation including the functional consequences of various pathological tau changes (e.g. mutations, post-translational modifications (PTMs), and protein-protein interactions). PTMs can regulate several aspects of tau biology such as proteasomal and autophagic clearance, solubility, and aggregation. Moreover, PTMs can contribute to the transition of tau from normal to pathogenic conformations. However, our understating of how PTMs specifically regulate the transition of tau into pathogenic conformations is partly impeded by the relative lack of structured frameworks to assess and quantify these conformations. In this review, we describe a set of approaches that includes several in vitro assays to determine the contribution of PTMs to tau's transition into known pathogenic conformations. The approaches begin with different methods to create recombinant tau proteins carrying specific PTMs followed by validation of the PTMs status. Then, we describe a set of biochemical and biophysical assays that assess the contribution of a given PTM to different tau conformations, including aggregation, oligomerization, exposure of the phosphatase-activating domain, and seeding. Together, these approaches can facilitate the advancement of our understanding of the relationships between PTMs and tau conformations.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Tauopatias / Doença de Alzheimer Limite: Humans Idioma: En Revista: Biochem Soc Trans Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Tauopatias / Doença de Alzheimer Limite: Humans Idioma: En Revista: Biochem Soc Trans Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos