Genetic Clue to Cell Death in Alzheimer's Disease Found
Scientists investigating the genes that regulate programmed cell death--the normal process by which old or unwanted cells die on schedule so the body can reshape developing tissues--have discovered a gene fragment that is nearly identical to a piece of one gene recently linked to Alzheimer's disease. This finding, published Jan. 26, 1996 in Science by a group from the National Institute of Allergy and Infectious Diseases (NIAID), is the first direct evidence that disregulation of this natural process may play a critical role in the development of Alzheimer's disease.
"We were taken by surprise," admits immunologist and senior author Luciano D'Adamio, M.D., Ph.D., chief of NIAID's T Cell and Molecular Biology Unit in the Laboratory of Cellular and Molecular Immunology (LCMI). "Our work suggests how an inherited form of Alzheimer's disease could arise from the uncontrolled and premature death of neurons."
"This unexpected result is another example of the often unpredictable but inevitable benefits of investment in basic research," comments Anthony S. Fauci, M.D., director of NIAID.
It is the first objective piece of evidence that some part of the programmed cell death pathway is involved in Alzheimer's disease. Human population data had suggested this, but the current finding provides a mechanism to explain the previous observations.
Alzheimer's disease is the single greatest cause of mental impairment in older people, affecting more than 2.5 million Americans. Familial or early-onset Alzheimer's disease is an extremely aggressive inherited form of the illness that strikes people between ages 30 and 60. It accounts for up to 20 percent of all cases of Alzheimer's disease. It progresses faster than the more common sporadic, late-onset form of the disease, which generally develops after age 65. Otherwise, however, the two types of the illness--which robs individuals of their memories and leads to mental confusion--are indistinguishable, characterized by neuronal degeneration and the development of plaques and tangles in the brain.
The NIAID group was interested in studying the genes that direct the programmed cell death pathway because aberrations in this pathway have been implicated in many other diseases as well. Examples include immunodeficiency diseases such as AIDS, neurodegenerative diseases such as Parkinson's, autoimmune diseases and cancers. Programmed cell death is carried out by apoptosis, a process that has been recognized for decades but only well-studied since the late 1980s. During apoptosis, the cell shrinks and its nucleus condenses. Within hours, the cell dies as the nucleus and other cell components break apart.
A model system in mice to isolate the genes involved in the programmed cell death pathway had been developed by the NIAID group, which also includes Pasquale Vito, Ph.D., and Emanuela Lacaná, Ph.D. Using this system, they had isolated six such genes to date. The current paper reports on their more detailed study of two of these genes: ALG-2, which codes for a calcium-binding protein, and ALG-3, what they now know to be the mouse version of a human gene, STM2, recently linked to Alzheimer's disease.
The NIAID group found the two genes in December 1994. At that time, they combed the library of known amino acid sequences of human disease genes but found no significant genetic overlap. Only last August, when several papers were published in Science and Nature that linked a subtype of familial Alzheimer's disease to the STM2 gene on chromosome 1, did the NIAID team discover the 98 percent match between a 103-amino-acid fragment of one of the genes they were studying and a portion of STM2.
STM2 occurs mainly in descendants of a colony of 18th and 19th century Germans who immigrated to a valley near the Volga River in Russia and later came to the United States. Interestingly, STM2 also is very similar (67 percent homology) to a different gene on chromosome 14 found last summer to be linked to another subtype of familial Alzheimer's disease, which may mean that the proteins these genes encode have similar functions.
The investigators also found the first calcium-binding gene, ALG-2, proven to be involved in programmed cell death. The authors say it may represent a prototype of a family of genes that mediate calcium-regulated signals along the death pathway. Dr. D'Adamio predicts they will find a disease associated with this gene as well.
NIAID is a component of the National Institutes of Health. NIAID conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Public Health Service, part of the Department of Health and Human Services.
References:
Vito P, Lacaná E, D'Adamio L. Interfering with apoptosis: Ca2+-binding protein ALG-2 and Alzheimer's disease gene ALG-3. Science 1996;271:521-5.
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