Tau Protein Modifications and Interactions: Their Role in Function and Dysfunction

Abstract

Tau protein is abundant in the central nervous system and involved in microtubule assembly and stabilization. It is predominantly associated with axonal microtubules and present at lower level in dendrites where it is engaged in signaling functions. Post-translational modifications of tau and its interaction with several proteins play an important regulatory role in the physiology of tau. As a consequence of abnormal modifications and expression, tau is redistributed from neuronal processes to the soma and forms toxic oligomers or aggregated deposits. The accumulation of tau protein is increasingly recognized as the neuropathological hallmark of a number of dementia disorders known as tauopathies. Dysfunction of tau protein may contribute to collapse of cytoskeleton, thereby causing improper anterograde and retrograde movement of motor proteins and their cargos on microtubules. These disturbances in intraneuronal signaling may compromise synaptic transmission as well as trophic support mechanisms in neurons.

Cl-NQTrp Alleviates Tauopathy Symptoms in a Model Organism through the Inhibition of Tau Aggregation-Engendered Toxicity

“…These diseases are characterized by the self-assembly of monomers of certain proteins, termed amyloids, into toxic oligomers and fibrils composed of β-sheet structures [12,13], such as the Aβ peptide and the tau protein in AD and α-synuclein in Parkinson's disease. In tauopathies, not only do intracellular toxic accumulations of tau protein appear, but the abnormal phosphorylation of tau also leads to MT disassembly due to its decreased tubulin-binding capacity [7,8]. Aggregation of tau is believed to cause neuronal toxicity in two main ways: (1) tau aggregation sequestrates monomers from their normal function of promoting MT stability, and (2) tau aggregates by themselves were shown to be neurotoxic [14,15].…”

“…Tubulin binding by tau is regulated by its phosphorylation state, which, in turn, is modulated by the coordinated action of kinases and phosphatases on the tau molecule [7]. Under pathological conditions, intracellular aggregates of abnormally hyperphosphorylated tau appear in the brain within the cell bodies and dendrites of neurons [7,8]. This is the main neuropathological characteristic of a group of heterogeneous dementias and movement disorders, termed tauopathies, which belong to the family of protein-misfolding disorders [9,10,11].…”

Pseudomonas aeruginosa exoenzymes U and Y induce a transmissible endothelial proteinopathy

“…Such variability has largely been attributed to the tau isoform expressed in the cell or organ evaluated (13), the degree and site(s) of posttranslational modification, including phosphorylation (27), and the susceptibility of the tau oligomer to proteolytic cleavage (20) (see Ref. 38 and references therein for discussion of each topic). Each of these issues is likely to be extremely important in determining the fate or biological activity of the high-molecular-weight endothelial tau, as some oligomers show significant cytotoxicity, whereas others are less detrimental.…”

Systematic Analysis of GWAS Data Reveals Genomic Hotspots for Shared Mechanisms between Neurodegenerative Diseases

“…The resulting enhanced neuronal activity has been shown to further accumulate interstitial fluid amyloid beta (ISF Aβ), while this accumulation of ISF Aβ is also linked with up-regulation of CRH gene expression [42], effectively establishing a feedback loop that can enhance negative dysregulation events. MAPT hyper-phosphorylation also increases its dissociation from microtubules, a process that has been linked to lewy-bodies and Parkinsonism, in the PD context [43].…”