Tau protein

Tau protein
source
Name	Tau protein
HGNCid	6893
EntrezGene	4137
OMIM	157140
RefSeq	NM_001123066
UniProt	P10636
Chromosome	17
Band	21.1

Tau protein. It is a microtubule-associated protein predominantly expressed in neurons of the central nervous system. Encoded by the MAPT gene on chromosome 17, it plays a critical role in stabilizing the cytoskeleton and facilitating axonal transport. Its abnormal aggregation into neurofibrillary tangles is a defining pathological hallmark of Alzheimer's disease and related tauopathies.

Structure and isoforms

The MAPT gene undergoes complex alternative splicing, generating six major isoforms in the adult human brain. These isoforms differ by the inclusion or exclusion of exons 2, 3, and 10, which encode specific protein domains. The inclusion of exon 10 results in isoforms containing four microtubule-binding repeats, termed 4R tau, while its exclusion produces isoforms with three repeats, termed 3R tau. The normal adult human brain maintains an approximately equal ratio of 3R to 4R tau. The protein's structure is divided into an N-terminal projection domain, a proline-rich region, the microtubule-binding domain, and a C-terminal region. This modular architecture allows tau to interact with various cellular components beyond microtubules, including the plasma membrane and synaptic vesicles.

Function in neurons

In healthy neurons, tau's primary function is to bind to and stabilize polymerized tubulin, thereby promoting microtubule assembly and stability. This stabilization is essential for maintaining axonal integrity and providing tracks for intracellular transport via motor proteins like kinesin and dynein. Tau also regulates microtubule dynamics by spacing out other microtubule-associated proteins. Beyond its canonical role, tau localizes to the axon initial segment and dendritic spines, where it is involved in signal transduction pathways and may modulate synaptic plasticity. Its phosphorylation state, regulated by kinases such as GSK-3β and CDK5, and phosphatases like PP2A, dynamically controls its affinity for microtubules.

Role in neurodegenerative diseases

The pathological aggregation of tau is central to a class of disorders known as tauopathies, the most prevalent of which is Alzheimer's disease. In Alzheimer's disease, hyperphosphorylated tau dissociates from microtubules and forms insoluble paired helical filaments, which coalesce into neurofibrillary tangles within neuronal cell bodies. The progression of tau pathology, described by the Braak staging system, correlates strongly with cognitive decline. Other major tauopathies include progressive supranuclear palsy, corticobasal degeneration, and Pick's disease, each associated with distinct isoform aggregates; for instance, Pick's disease primarily involves 3R tau aggregates. The transcellular propagation of pathological tau species along neural circuits is thought to drive disease progression.

Pathological modifications

Several post-translational modifications drive tau from a soluble to an aggregated state. Hyperphosphorylation at numerous serine and threonine residues, mediated by kinases including GSK-3β, CDK5, and MARK, reduces its microtubule-binding capacity and promotes self-assembly. Other critical modifications include acetylation at lysine residues, which impairs degradation and facilitates aggregation, and truncation by proteases like caspases and calpain. Ubiquitination marks abnormal tau for degradation by the proteasome or autophagy pathways, but these systems become overwhelmed in disease. The formation of oligomers, which may be more toxic than larger fibrils, is an early event in the pathogenic cascade.

Detection and biomarkers

Advances in cerebrospinal fluid analysis and neuroimaging have enabled the detection of tau pathology in living individuals. Immunoassays of cerebrospinal fluid can measure levels of total tau and phosphorylated tau, with elevated phosphorylated tau being a specific biomarker for Alzheimer's disease pathology. The development of PET ligands, such as flortaucipir (AV-1451), allows for the in vivo visualization of neurofibrillary tangles using positron emission tomography. These tools are integral to the diagnostic framework proposed by the National Institute on Aging and the Alzheimer's Association, which defines Alzheimer's disease by its biological pathology. Blood-based assays for phosphorylated tau are also emerging as promising, less invasive diagnostic tools.

Therapeutic approaches

Therapeutic strategies targeting tau are diverse and aim to modify disease progression. Tau immunotherapy, using either active vaccines or passive antibodies, seeks to promote clearance of extracellular pathological tau. Small molecules are being developed to inhibit pathological tau aggregation or to enhance microtubule stability. Other approaches aim to correct the imbalance of tau isoforms, particularly for 4R tauopathies, using antisense oligonucleotides targeting the MAPT pre-mRNA. Modulating the activity of key kinases like GSK-3β or enhancing autophagy and proteasome function are additional avenues being explored in clinical trials sponsored by entities like the Tau Consortium.

Category:Proteins Category:Neuroscience Category:Neurodegenerative disorders