Tau Fibrillogenesis
The protein tau is the most abundant microtubule associated protein in the central and peripheral nervous system. In the brain, tau plays a role in the assembly and stabilization of microtubules. The function of tau, however, appears to overlap with other
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Tau Fibrillogenesis Nitin Chaudhary and Ramakrishnan Nagaraj
Abstract The protein tau is the most abundant microtubule associated protein in the central and peripheral nervous system. In the brain, tau plays a role in the assembly and stabilization of microtubules. The function of tau, however, appears to overlap with other microtubule binding proteins. The observation that tau is associated with neurodegenerative diseases has renewed interest in this protein. Various aspects of structure and biochemistry of tau, fibril formation and clinical perspectives, including therapeutic strategies are reviewed in this chapter. Keywords Tau · Alzheimer’s disease · Neurofibrillary tangles · Paired helical filaments Abbreviations NFTs AD PHFs EM
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Neurofibrillary tangles Alzheimer’s disease Paired helical filaments Electron microscopy
Introduction
The protein tau, was first identified as a microtubule-assembling factor (Weingarten et al. 1975). It was designated by the Greek letter tau (τ) for its ability to induce tubule formation. Tau is the most abundant microtubule associated protein (MAP) in the central and peripheral nervous system. In the brain, it is predominantly present in the neuronal axons where it is involved in the assembly of microtubules and their N. Chaudhary () Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati 781 039, Assam, India e-mail: [email protected]; [email protected] R. Nagaraj CSIR - Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India e-mail: [email protected] J. R. Harris (ed.), Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease, Subcellular Biochemistry 65, DOI 10.1007/978-94-007-5416-4_4, © Springer Science+Business Media Dordrecht 2012
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stabilization and thereby giving the neurons their characteristic structure. In fact, most of the tau protein in cells is always associated with microtubules. In cell-free assays, binding of tau to microtubules results in their polymerization and stabilization (Weingarten et al. 1975). Cell culture studies have shown that depletion of tau using siRNA does not show significant effect on cultured neurons. However, depletion of tau makes the neuronal microtubules more susceptible to katanin catalyzed breakdown (Qiang et al. 2006). Katanin is a microtubule-severing protein that exists as a heterodimer of a 60 kDa ATPase subunit and an 80 kDa subunit that targets the protein to centrosomes (McNally and Vale 1993). Oligomerization of katanin on microtubules followed by ATP hydrolysis by the 60 kDa ATPase subunit is the mechanism proposed for its microtubule severing activity (Hartman and Vale 1999). Microtubules act as the scaffold for the oligomerization of the katanin while ATP hydrolysis provides the energy required to severe the microtubules (Hartman and Vale 1999). Binding of tau to microtubules would make the microtubules inaccessible to katanin thereby stabilizing them. The extensive studies performed on tau in past t
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