| tau protein | |
|---|---|
| Gene | MAPT |
| UniProt ID | P10636 |
| PDB IDs | 4NP6, 5O3L, 6HVM |
| Molecular Weight | 45-65 kDa (isoform dependent) |
| Subcellular Localization | Axons, Neurons |
| Protein Family | MAPT family |
| Associated Diseases | Alzheimer's Disease, FTD, CBD, PSP, PART |
Tau Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
tau protein is a microtubule-associated protein encoded by the MAPT gene that plays essential roles in stabilizing microtubules in neuronal cells. In Alzheimer's Disease and
other neurodegenerative conditions known as tauopathies, tau becomes hyperphosphorylated, aggregates into neurofibrillary tangles (NFTs), and contributes to neuronal death. The tau protein is therefore one of the most intensively studied proteins in neuroscience due to its central role in neurodegeneration[1].
Tau proteins are primarily expressed in neurons, where they bind to microtubules and promote their polymerization and stability. The protein exists in multiple isoforms generated by alternative splicing, ranging from 352 to 441 amino acids in length. This alternative splicing is developmentally regulated and tissue-specific, with six isoforms expressed in the adult human brain[2].
The human MAPT gene located on chromosome 17q21.31 produces multiple tau isoforms through alternative splicing of exons 2, 3, and 10. These isoforms differ in the presence or
absence of one or two N-terminal inserts (exons 2 and 3) and either three or four microtubule-binding repeat domains (exon 10). The regulation of exon 10 splicing is particularly
important, as it determines whether the protein contains three (3R tau or four (4R tau repeat domains. The balance between 3R and 4R tau is critical, as imbalances are associated
with several tauopathies[3].
tau protein consists of several distinct domains:
Tau undergoes numerous post-translational modifications that regulate its function:
The primary physiological function of tau is to bind to and stabilize microtubules, the cytoskeletal filaments essential for intracellular transport and neuronal morphology. Tau
promotes microtubule assembly and prevents microtubule disassembly by binding to the tubulin heterodimers. This function is crucial in neurons, where microtubules span long
distances from the cell body to synaptic terminals and are essential for axonal transport[6].
Beyond microtubule stabilization, tau participates in various neuronal signaling processes:
In Alzheimer's Disease, tau undergoes dramatic pathological changes:
Hyperphosphorylation: Abnormal phosphorylation by kinases such as GSK-3β, CDK5, and MAP kinases reduces tau's affinity for microtubules and promotes aggregation. Over 40 phosphorylation sites show increased modification in AD brain.
Neurofibrillary Tangles: Hyperphosphorylated tau self-associates into paired helical filaments (PHFs) and straight filaments (SFs) that accumulate as neurofibrillary tangles (NFTs). These insoluble aggregates are a hallmark of AD neuropathology.
Tau Spreading: Propagation of tau pathology follows a predictable pattern in AD, spreading from the entorhinal cortex to the hippocampus and throughout the neocortex. This prion-like spread involves extracellular tau seeds that are taken up by neighboring neurons[8].
Tau pathology is a feature of multiple neurodegenerative diseases:
Tau aggregation leads to neuronal dysfunction through multiple mechanisms:
Multiple therapeutic approaches are being developed:
Active and passive tau immunotherapy represents a promising strategy:
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Gotz J, Xiaolin L, Ittner LM. New insights into the protein tau system. Neuron. 2008;58(4):575-577. 2008. ↩︎
Hutton M, Lendon CL, Rizzu P, et al. Association of missense and 5'-splice-site mutations in tau with inherited dementia FTDP-17. Nature. 1998;393(6686):702-705. 1998. ↩︎
Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Post-translational modifications of tau protein in Alzheimer's disease. J Neural Transm. 2005;112(6):813-838. 2005. ↩︎
Cohen TJ, Guo JL, Hurtado DE, et al. The acetylation of tau inhibits its function and promotes pathological aggregation. Nat Commun. 2011;2:252. 2011. ↩︎
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Schmitt HP. On the paradox of iLBE: looking for neuronal loss in Alzheimer's disease by extrapolating exponential survival. Sci Rep. 2021;11(1):18344. 2021. ↩︎
Huang Y, Wu L, Wu J, et al. Tau pathology in Alzheimer's disease: A neighbor or partner in crime? Prog Neuropsychopharmacol Biol Psychiatry. 2023;121:110641. 2023. ↩︎
Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ. Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A. 2011;108(14):5819-5824. 2011. ↩︎