Cellular Biology of Tau Diversity and Pathogenic Conformers

Abstract

Tau accumulation is a prominent feature in a variety of neurodegenerative disorders and remarkable effort has been expended working out the biochemistry and cell biology of this cytoplasmic protein. Tau's wayward properties may derive from germline mutations in the case of frontotemporal lobar degeneration (FTLD-MAPT) but may also be prompted by less understood cues—perhaps environmental or from molecular damage as a consequence of chronological aging—in the case of idiopathic tauopathies. Tau properties are undoubtedly affected by its covalent structure and in this respect tau protein is not only subject to changes in length produced by alternative splicing and endoproteolysis, but different types of posttranslational modifications that affect different amino acid residues. Another layer of complexity concerns alternate conformations—“conformers”—of the same covalent structures; in vivo conformers can encompass soluble oligomeric species, ramified fibrillar structures evident by light and electron microscopy and other forms of the protein that have undergone liquid-liquid phase separation to make demixed liquid droplets. Biological concepts based upon conformers have been charted previously for templated replication mechanisms for prion proteins built of the PrP polypeptide; these are now providing useful explanations to feature tau pathobiology, including how this protein accumulates within cells and how it can exhibit predictable patterns of spread across different neuroanatomical regions of an affected brain. In sum, the documented, intrinsic heterogeneity of tau forms and conformers now begins to speak to a fundamental basis for diversity in clinical presentation of tauopathy sub-types. In terms of interventions, emphasis upon subclinical events may be worthwhile, noting that irrevocable cell loss and ramified protein assemblies feature at end-stage tauopathy, whereas earlier events may offer better opportunities for diverting pathogenic processes. Nonetheless, the complexity of tau sub-types, which may be present even within intermediate disease stages, likely mitigates against one-size-fits-all therapeutic strategies and may require a suite of interventions. We consider the extent to which animal models of tauopathy can be reasonably enrolled in the campaign to produce such interventions and to slow the otherwise inexorable march of disease progression.

Single-nucleus chromatin accessibility profiling highlights distinct astrocyte signatures in progressive supranuclear palsy and corticobasal degeneration

“…7 c) [ 6 , 55 , 62 ]. Responses to pathological stimuli associated with the occurrence of pTau are likely related to astrocytic subpopulations, as delineated by differential use of TF binding sites in our study [ 15 , 17 , 30 ]. Nevertheless, we cannot exclude the possibility that accessibility changes in astrocytes are secondary in nature, without any direct effect of pTau on the compaction of chromatin, even though this has been described before in Tau transgenic Drosophila [ 19 ].…”

Prion-like strain effects in tauopathies

“…Exons 0 and 14 are transcribed but not translated as they are a part of the 5′-untranslated sequence (5′-UTR) and the 3′-untranslated sequence (3′-UTR), respectively (Liu and Gong 2008 ; Sud et al 2014 ). In the adult human brain, alternative splicing of exons 2, 3, and 10 gives rise to all six isoforms of tau; exons 4A, 6, and 8 are exclusive to the peripheral nervous system and absent in the human brain (Kang et al 2020a ). b A schematic representation of native soluble monomeric 4R tau adapting a different conformation and forming insoluble aggregates.…”

Tau: A Signaling Hub Protein

“…In addition, aggregates composed of tau pseudophosphorylated at S422, a modification found in pre-tangle neurons affected early in AD, also inhibited both aFAT and rFAT when perfused in isolated axoplasm, but a potential involvement of PAD on these effects has not yet been evaluated (Tiernan et al, 2016). The highly dynamic conformational flexibility of tau, differentially impacted by phosphorylation of specific residues, might confer upon this protein its ability to work as a signaling hub and activate and/or modulate different signaling pathways (Smith et al, 2006;Kang et al, 2020). Collectively, these and other studies suggest a complex relationship between specific phosphorylation events in tau and their net impact on tau conformation, as well as the potential co-existence of additional biologically active domains in tau that, like PAD, may promote activation of other signaling pathways (Morris et al, 2020).…”