Abstract
Tau plays a central role in a group of neurodegenerative disorders collectively named tauopathies. Despite the wide range of diverse symptoms at the onset and during the progression of the pathology, all tauopathies share two common hallmarks, namely the misfolding and aggregation of Tau protein and progressive synaptic dysfunctions. Tau aggregation correlates with cognitive decline and behavioural impairment. The mechanistic link between Tau misfolding and the synaptic dysfunction is still unknown, but this correlation is well established in the human brain and also in tauopathy mouse models. At the onset of the pathology, Tau undergoes post-translational modifications (PTMs) inducing the detachment from the cytoskeleton and its release in the cytoplasm as a soluble monomer. In this condition, the physiological enrichment in the axon is definitely disrupted, resulting in Tau relocalization in the cell soma and in dendrites. Subsequently, Tau aggregates into toxic oligomers and amyloidogenic forms that disrupt synaptic homeostasis and function, resulting in neuronal degeneration. The involvement of Tau in synaptic transmission alteration in tauopathies has been extensively reviewed. Here, we will focus on non-canonical Tau functions mediating synapse dysfunction.
Highlights
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While in Alzheimer’s disease (AD) both 3R and 4R contribute to aggregation, 4R isoforms are predominant in PSP, CBD, AGD and GGT and 3R are predominant in Pick disease
Self-aggregation is inhibited by the presence of charged intact N-terminal and Cterminal domains; when Tau undergoes post-translational modifications (PTMs), in particular hyperphosphorylation, acetylation and truncation, the conformational structure changes and exposes the sticky repeat regions, which result in the formation of aggregates [13]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Concomitant Tau and TRIM28 increased levels have been measured in neuronal nuclei of AD human brains supporting their close dependence in nuclear transport and suggesting a pathological involvement of Tau in chromatin remodelling [108].
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