Cytoskeletal Proteins Involved in Neurodegenerative Diseases like Dementia

Tau proteins are cytoskeletal proteins involved in the stability of microtubules in neurons. This function makes tau proteins important components of neuron morphology and nerve cell construction. Because of this relationship and the role neuronal morphology (i.e. axons and dendrites) plays in neural networks, changes in tau protein can cause alterations in how neurons interact and the integrity of the nerve cell structure. In pathological conditions tau proteins may self-aggregate (i.e. bind to each other), forming filaments that interrupt the cell structure and intracellular transport.

Characteristics of tau proteins

Tau proteins consist of various isorforms due to alternative RNA splicing, varying by which exons are excluded. The RNA transcript is from a single gene. Some forms of tau are expressed more during fetal development or more during adulthood. Tau is also known as neurofibrillary tangle protein, but it gets its name from its full designation – paired helical filament-tau. The gene designation is MAPT or TAU. Phosphorylation of serine and threonine residues at serine-proline and threonine-proline motifs is a normal post-translational modification. The isoforms are also characterized as type I or type II based on the number of repeats in the microtubule-binding domain. This characterstic provides tau two different ways to interact with microtubules.

Importance of microtubules in nerve cells

Microtubules are normal cell components made of filaments of tubulin. These cytoskeletal structures have been found to be important in the distal portions of axons. They are also essential for the transport of neurotransmitters from the cell body to the synapse. Thus, disruption of the microtubules can disrupt neurotransmission. Tau protein has been found to be necessary for microtubule assembly and possibly cell polarity. In certain neurodegenerative disorders, such as Alzheimer’s disease, neurofibrillary tangles have been observed, an aberrant and improperly functioning form of the tubulin-tau network.

Tauopathies and nerve degeneration

Diseases caused by mutations in the tau gene on chromosome 17 and/or disruption of the structure and/or function of the tau protein(s) are called tauopathies. A number of neurodegenerative diseases are associated with filamentous tau aggregation, including Alzheimer’s disease and some dementias. Disruption of the cytoskeleton by aggregates can activate degenerative cellular processes that result in neuron loss. Research has found that hyperphosphorylation of tau protein may be the culprit underlying tauopathies. Pathological tau proteins undergo glycation post-translation, and hyperphosphorylated tau is polyubiquitinated, which may trigger degradation by the polysome. In addition, a lack of the molecular chaperones known as heat shock proteins is known to play a role in tau aggregation. However, exactly how tau causes neurodegeneration is not yet known.

An extensive review of the tau gene and resulting protein was published in Physiological Reviews in 2004.