Tau Gene Linked To Family Of Neurodegenerative Disorders; Finding May Yield Insight Into Onset Of Alzheimer's Disease

October 27, 1998

Researchers led by a UC San Francisco neurologist are reporting findings that they say may put them an important step closer to understanding the way in which Alzheimer's disease ravages the brain cells of patients.

In a paper published in the October 27 issue of Proceedings of the National Academy of Sciences, the researchers announce that they have identified three mutations in a gene that produces the tau protein, and have determined that these mutations cause several related hereditary neurodegenerative diseases, the most prevalent known as frontotemporal lobe dementia.

While the finding does not directly implicate the tau gene in Alzheimer's disease, it does so strongly by association, said the senior author of the study, Kirk Wilhelmsen, MD, an assistant professor neurology at UCSF. The tau protein has long been a suspected factor in Alzheimer's disease because abnormal, insoluble, tangled filaments of the protein-are always found in the autopsied brains of people who have the disease. But because researchers have never found a mutation in the tau gene of Alzheimer's patients, they had come to think that the neurofibrillary tangles, composed primarily of tau protein, were but an inconsequential by-product of some other factor that actually caused nerve cell degeneration.

Now that there is hard evidence that tau, itself, is capable of killing brain cells, the picture changes, said Wilhelmsen. "Finding a direct link between mutations in the tau gene and these hereditary neurodegenerative diseases strongly indicates that tau is an important player in neurons dying in Alzheimer's disease and many other diseases, as well," he said.

The goal now, he said, is to figure out what causes tau protein to accumulate in insoluble filaments in the brain cells of Alzheimer's patients. While mutations in tau gene appear to lead directly to cell death in the hereditary diseases studied, Wilhelmsen said he and colleagues don't believe that a tau mutation occurs in Alzheimer's disease. Rather, they suspect that other factors, such as mutations in the gene for amyloid protein, affects the biology of the tau gene, causing the tau protein to become destructive and kill brain cells.

Besides offering new direction for exploring Alzheimer's disease, of course, the findings offer a more immediate direction for exploring treatments for the hereditary dementias associated with the three tau mutations. More broadly, the findings also might provide a model for understanding how other abnormal protein filaments might kill cells in a range of diseases, including other sporadic dementias, Parkinson's disease and Huntington's disease, said Wilhelmsen.

The study, conducted by a multi-institutional team of researchers, including scientists at Veterans Affairs Puget Sound Health Care System, The University of California Los Angeles and The University of Pennsylvania focused on genetic patterns and brain samples of families with a class of hereditary neurodegenerative diseases known collectively as "frontotemporal dementia and parkinsonism linked to chromosome 17."

The diseases vary in the symptoms they cause--frontotemporal dementia, for instance, prompts patients to withdraw socially and to become disinhibited as they lose their cognitive abilities, and pallido-ponto-nigral degeneration manifests itself as parkinsonism, sometimes with personality changes. The diseases also vary in terms of the specific brain regions affected.

But in many patients with the hereditary dementia disorders, certain subpopulations of dead neurons and glial cells contain abnormal deposits of the insoluble, tangled tau protein in the cells' cytoplasm, the region outside the nucleus. (Normally, tau protein helps stabilize microtubules, which are vital for transportation of molecules within cells and maintaining the shape of cells.)

Wilhelmsen and other members of the presenting team previously determined that these diseases all result from genetic information encoded in a specific area of chromosome 17, and they knew that the tau gene was located in this region. In the current study, they have identified three different tau mutations that correspond with various forms of the disease in a number of different families. They identified two mutations that correlate with "pallido-ponto-nigral degeneration" and four forms of "frontotemporal dementia parkinsonism linked to chromosome 17." They identified a third mutation that correlates with yet another form of frontotemporal dementia. Some of these mutations have recently been identified in other families.

They also determined that the key difference between the six normal versions of tau gene and the three mutated versions is a sequence of the gene that encodes a portion of tau protein that binds to microtubules. Microtubules are protein filaments that help provide support for cell structures such as axons, the long projections that form connections between neurons. The mutated versions produce tau proteins with 4 microtubule binding repeats, as opposed to 3 microtubule binding repeats.

This is a potentially major finding, said Wilhelmsen, because it could lead to the development of drugs that would aim to alter the genetic sequence. The first step would be the development of animal models of these diseases. "The key point is that there doesn't have to be a different tau protein, we just have to change how the tau gene is made," said Wilhelmsen.

While it is still unclear how abnormal tau protein actually exacts its toll on cells, there are two theories: One, that aggregation of tau protein is itself toxic, and can cause cell death. (Huntington's disease, spinalcerebral degeneration and Parkinson's disease all appear to result, in some way, from protein accumulation.) The other, that abnormal tau protein doesn't bind microtubule proteins correctly.

The inability to bind to microtubules may cause microtubules to collapse, said Wilhelmsen. This, in turn, would destabilize axons, which are normally supported by the microtubules. Axons are the conduits through which nerve cells communicate. Without axon connections, neurons die.

The next step, said Wilhelmsen, is to further test the hypothesis that the mutated forms of the tau gene are leading directly to cell death. The evidence we have so far, he said, is compelling.

Co-authors of the study included lead authors Lorraine N. Clark, PhD, and Parvie Navas, postdoctoral fellows at UCSF and Veterans Affairs Puget Sound Health Care System, Seattle Division, as well as other researchers at numerous labs at the University of Washington, researchers at the University of Nebraska Medical Center, the Reed Neurological Research Center, The University of California Los Angeles, Hopital Charles LeMoyne, Quebec, Canada, Oregon Health Sciences University, Universiteit Amsterdam, E.K Shriver Center, Waltham, Mass., and The University of Pennsylvania.

The research was supported in part by National Institutes of Aging grants.

University of California - San Francisco

Related Neurons Articles from Brightsurf:

Paying attention to the neurons behind our alertness
The neurons of layer 6 - the deepest layer of the cortex - were examined by researchers from the Okinawa Institute of Science and Technology Graduate University to uncover how they react to sensory stimulation in different behavioral states.

Trying to listen to the signal from neurons
Toyohashi University of Technology has developed a coaxial cable-inspired needle-electrode.

A mechanical way to stimulate neurons
Magnetic nanodiscs can be activated by an external magnetic field, providing a research tool for studying neural responses.

Extraordinary regeneration of neurons in zebrafish
Biologists from the University of Bayreuth have discovered a uniquely rapid form of regeneration in injured neurons and their function in the central nervous system of zebrafish.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Neurons thrive even when malnourished
When animal, insect or human embryos grow in a malnourished environment, their developing nervous systems get first pick of any available nutrients so that new neurons can be made.

The first 3D map of the heart's neurons
An interdisciplinary research team establishes a new technological pipeline to build a 3D map of the neurons in the heart, revealing foundational insight into their role in heart attacks and other cardiac conditions.

Mapping the neurons of the rat heart in 3D
A team of researchers has developed a virtual 3D heart, digitally showcasing the heart's unique network of neurons for the first time.

How to put neurons into cages
Football-shaped microscale cages have been created using special laser technologies.

A molecule that directs neurons
A research team coordinated by the University of Trento studied a mass of brain cells, the habenula, linked to disorders like autism, schizophrenia and depression.

Read More: Neurons News and Neurons Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.