The ALS Association

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Common Link Discovered in ALS and Frontotemporal Dementia

By: Roberta Friedman, Ph.D.
October 6, 2006

[Quick Summary: A new discovery of a protein present in both ALS and in the type of dementia that can also occur in this neurological disease gives hope that new therapies can be designed to address the common disease processes.]

Researchers are publishing in the journal Science October 6 on a protein that is involved in a type of cognitive change, called frontotemporal dementia (FTD) that can occur in ALS. The finding gives a common clue to the two disorders that can go together, opening doors to new therapeutic approaches for both.

The protein is called TDP-43 and plays a role in processing DNA instructions to create other proteins. Its presence in damaged tissues in both FTD and ALS points to a common biology that has become suspect, as scientists in the past five years have come to the conclusion that something must be held in common between the two disorders.

“Identification of TDP-43 as the disease protein provides a biochemical link between ALS and FTD as a clinico-pathological spectrum of the same disorder,” said Virginia Lee, Ph.D., a neuroscientist at the University of Pennsylvania in Philadelphia and senior author of the report in Science, “with new opportunities for the development of better diagnostics and for drug discovery.”

Many people with FTD have motor neuron disease, and often people with the motor neuron disease, amyotrophic lateral sclerosis (ALS, also called Lou Gehrig’s disease), have subtle cognitive change that most resembles FTD.

FTD differs from the dementia in Alzheimer’s disease in that memory stays intact, but other higher order functions such as decision making, foresight and speech can become severely impaired. The proteins involved in the two dementias can now be shown to differ as well.

German researcher Manuela Neumann, M.D., working with Lee, John Trojanowski, M.D., Ph.D., and an international team of collaborators, saw that the TDP-43 protein occurs in abnormal deposits of protein in both FTD and in ALS. Both of the disorders are marked by abnormal deposits, but scientists did not know the identity of the proteins responsible. Now that a common protein is identified, the disease process can be further clarified, and researchers can see if they can devise therapies that will interrupt or slow the process.

The TDP-43 protein is labeled by ubiquitin, which marks damaged proteins for destruction. Ubiquitin labeled deposits were known to be present in both ALS and in some forms of FTD. Now that researchers know the identity of the protein that is marked by ubiquitin, they can focus effort on its role in ALS and FTD.

Not much is known about TDP-43, save that it is somehow involved in translating DNA instructions to make other proteins in the cells. It is usually found in the cell nucleus, but the abnormal deposits in FTD and in ALS are instead outside the nucleus.

Other recent findings about FTD may prove relevant to ALS. Mutations lately identified in the progranulin gene, coding a growth factor, and in CHMP2B can produce FTD. So far no progranulin mutations are evident in ALS, but two ALS patients have shown mutations in CHMP2B, a protein involved in moving key materials within cells.

The common threads emerging rapidly from both the genetics and the pathology of FTD and ALS are that some aspect of nourishment of key nerve cells is impaired, resulting in production of damaged protein. Tagging by ubiquitin is the first step in managing the damage.

The mounting evidence linking ALS to FTD in the past five years and especially this new discovery are possible only through the concern for others shown by ALS patients and families who have donated tissue after death. Materials from patients in the Greater Philadelphia Chapter of The ALS Association contributed to the findings now published by Lee’s group. The materials were provided through The ALS Association Center at the Penn Neurological Institute, directed by Leo F. McCluskey, M.D., an author on the report in Science.

Dr. Lee noted that donations made “some time ago allowed us to move forward with this study on the ALS component.”

Questions and Answers

Q--Will someone with ALS develop dementia?

A--Most people with ALS do not get FTD. Estimates are that a third of ALS patients have some mild cognitive impairment. This is not full blown FTD, just a mild form.

It is quite possible that people with ALS die before their cognitive change becomes appreciable, but no one knows.

The Penn researchers report that all the ALS patients they have studied did have the protein, but it means that the protein is almost certainly involved in the disease process. It does not mean that all ALS patients get FTD. It means that there is a common biology behind the two diseases, which are apparently part of a spectrum of brain damage. In ALS, the motor neurons die, but in FTD other neurons are dying. In some cases, both types of neurons are affected and die.

See The ALS Association’s web site under the research tab for further information about cognitive changes in ALS.

M Neumann et al. Ubiquinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. Science DOI: 10.1126/science.1134108 (2006)

News article by Jean Marx

University of Pennsylvania press release

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