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               The Function of the Tau Protein

         

 

      Despite their presence in all cells, tau proteins are especially important in the central nervous system where they are associated with microtubules (tracks that guide nutrients and molecules from the body of the cell down to the ends of the axon)(http://www.mondofacto.com).  

 

    Six tau isoforms are known to exist in the brain tissue and each can be identified by its number of binding domains. The more binding domains and isoform has, the more efficient they are at stabilizing microtubules (www.absoluteastronomy.com).  

 

          In an unhealthy neuron, tau is chemically altered and joins with other tau proteins which subsequently become entwined resulting in a breakdown of microtubules, collapse of the internal support structure of the neuron, and eventually leads to malfunctions in communication between neurons and death of the cells (www.web-books.com).

 

 

 

http://www.pueblo.gsa.gov

 

     

 

Where is Tau Located? 

 

     Tau’s specific location in the neuron is the axon, where its ideal state is phosphorylated and highly soluble, a composition that allows the protein to stabilize and promote the polymerization of microtubules (Hanger, D. et al).

 

 

    http://www.ftd-picks.org/images/content/learnmore.genetics.3.gif

 

 

 

Phosphorylation: the addition of phosphate groups to amino acids

 

     The degree of phosphorylation is crucial in regulating microtubule stabilization and is regulated by a host of kinases, such as PKN and glycogen synthase kinase 3 (GSK3) (Hanger, D. et al). When PKN is activated hyperphosphorylation occurs, resulting in a chemical change in tau which causes the tangling of both paired helical and straight filaments, which is connected to the pathogenesis of Alzheimer’s disease and other tauopathies (www.absoluteastronomy.com).

 

Neurofibrillary tangles in a Neuron:

 

http://www.rndsystems.com/DAM_public/5213.jpg

 

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The Structure of Tau

 

 

 

Structural information on tau is limited, but due to its function in neurodegenerative diseases, it is important to determine its construction. Tau is known as an intrinsically disordered protein (IDP) and until recently it was impossible to determine the atomic structure of an IDP due to the difficulty in preparing the protein in the form required for X-ray and NMR techniques (Sevcik, J et al). Tau protein self-assembles into paired helical filaments (PHF)-like fibers, and is modified by phosphorylation. The use of this IDP property made it possible to attain regular tertiary structure, after binding events during self assembly or when joined with its target (Sevcik, J et al).

                

 

http://www.taurx.com

 

 

     Attempts to crystallize tau have resulted in paracrystals and a great degree of variation in the repeat of the paracrytals leads to the conclusion that tau is highly elastic (Hagstedt, T. et al).

          

 

           

 

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Taupathies: Diseases caused by mutations in Tau

 

 

Taupathy: a neurodegenerative disease in which intracellular pathological aggregates of tau protein are present in the brain

 

           The most renowned taupathy is Alzheimer's disease and it results in the most common form of dementia inflicted. Alzheimer's is the fourth largest cause of death for people over 65(Sonkusare, S.K. et al).

 

A brief overview of Alzheimer's Disease:

 

 

 

 http://www.realage.com/health_guides/Alzheimer/img%5CLivingWithAlzheimers_artv1.jpg

 

 

In addition to Alzheimer’s disease, tau abnormalities give rise to a number of other neurodegenerative diseases including:

 

• progressive supranuclear palsy (http://www.ninds.nih.gov)
• Picks disease (http://www.ninds.nih.gov)
• fronto-temporal dementia (http://www.mayoclinic.com)
• corticobasal degeneration (http://memory.ucsf.edu)

          

 

          All of the taupathies are caused by mutations in the tau gene. Each exhibits its own characteristics but all share obvious intracellular inclusions such as neurofibullary tangles or neuropil threads, which are the result of hyperphosphorylation and increase in protein insolubility (Hanger, D. et al). 

 

http://journals.prous.com 

 

Characteristic signs and symptoms of taupathies include:

 

• Changes in personality
• Changes in verbal abilities
• Changes in social behavior

• Difficulties in thinking/decision making
• Poor coordination and balance
• Psychiatric symptoms
• Dementia

          

      The development of several mouse models that produce tau tangles will allow researchers to address the many questions that remain about these diseases (www.web-books.com).

 

 

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Tau as a Therapeutic Target

    

 

Tau protein is an important constituent in the production of Alzheimer’s disease and other dementia related disorders. A new comprehension of how tau works has lead to the possibility of targeting the protein for therapeutic purposes (Larner, A.). The goal of the therapy is to improve cognitive and behavioral symptoms of patients. A new form of therapy aims at protecting those cells that cannot be replaced: ones belonging to the central and peripheral nervous system (Sonkusare, S.K. et al).

 

          Therapeutic targeting of tau can be achieved a number of ways including:           

 

1. Reduction of tau phosphorylation through inhibition of protein kinases such as GSK-3 and cyclin dependant kinase
2. Separation of tau aggregates 
3. Tau immunotherapy           

 

          Transgenic models provide the platform for these studies. In tangle-forming transgenic mice, a decrease in phosphorylation, the amount of insoluble tau and neurodegeneration results from the inhibition of GSK-3 (Hanger, D et al.).  

 

      By increasing activity of tau phosphatases there is a possiblity of preventing or reducing neuronal degeneration that leads to Alzheimer's Disease (Iqbal, K.).

 

 (http://www.emdbiosciences.com/sharedimages/calbiochem/pathway/Tau_Phosphorylation.gif)

 

 

An effective means of preventing the continuation of the pathogenic cascade that results from the early hyperphosphorylation of tau is to interrupt the stage at which hyperphosphorylation occurs by targeting tau kinases and inhibitors of tau hyperphosphorylation (Castro, A and Martinez, A).

 

 

     Despite advances, tau immunotherapy strategies remain underdeveloped. Targeting kinases remains the most practical mean of discovering ways to prevent tau-induced neurodegeneration (Hanger, D et al).