Abstract
Tau protein, found in both neuronal and non-neuronal cells, forms aggregates in neurons that constitutes one of the hallmarks of Alzheimer’s disease (AD). For nearly four decades, research efforts have focused more on tau’s role in physiology and pathology in the context of the microtubules, even though, for over three decades, tau has been localised in the nucleus and the nucleolus. Its nuclear and nucleolar localisation had stimulated many questions regarding its role in these compartments. Data from cell culture, mouse brain, and the human brain suggests that nuclear tau could be essential for genome defense against cellular distress. However, its nature of translocation to the nucleus, its nuclear conformation and interaction with the DNA and other nuclear proteins highly suggest it could play multiple roles in the nucleus. To find efficient tau-based therapies, there is a need to understand more about the functional relevance of the varied cellular distribution of tau, identify whether specific tau transcripts or isoforms could predict tau’s localisation and function and how they are altered in diseases like AD. Here, we explore the cellular distribution of tau, its nuclear localisation and function and its possible involvement in neurodegeneration.
Highlights
IntroductionTau (tubulin-associated unit) is a low molecular weight protein, first identified by Weingarten et al
Tau is a low molecular weight protein, first identified by Weingarten et al.which showed the capacity to promote microtubule assembly in vitro [1]
The tau gene, through complex post-transcriptional processing, yields predominantly three transcripts: a less abundant 2kb tau transcript which encodes for a tau mainly targetted to the nucleus [12]; 6kb transcript which encodes for tau predominantly directed to the soma/axons in the central nervous system (CNS) [11,13]; and 8/9 kb transcript producing a tau preferentially expressed in the retina and peripheral nervous system (PNS) and with apparent molecular weight of about 110–120 kDa, often called high molecular weight (HMW) tau [14,15]
Summary
Tau (tubulin-associated unit) is a low molecular weight protein, first identified by Weingarten et al. The alternate splicing of exon 2, 3 and 10 generates the six widely known isoforms of tau in the CNS, ranging from 352 to 441 amino acids in length and 60–74 kDa in weight on SDS-PAGE (Figure 1) [5,6]. Depending on the inclusion and/or exclusion of exon 2, 3 and 10, tau can have three or four (3R/4R) microtubule binding repeats and the presence or absence of 1 or 2 N-terminal inserts, leading to the six widely known isoforms of tau in the CNS. Electron microscopy reveals that PHFs (Figure 2b) are made up of a twisted ribbon-like structure (Figure 2a), whereby two filament twist around one another [25] Both tau filaments from human brain and from in vitro assembly of recombinant tau protein have cross-β structure [26]. We discuss the unconventional localisation and function of tau, especially, as it relates to the nucleus, and how it may play a role in neurodegenerative diseases like AD
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
