NEW YORK, June 23, 1999 -- A single alteration in the DNA alphabet occurring in a newly discovered human gene causes an unusual form of hereditary dementia characterized by amyloid deposits in the brain, one of the hallmarks of Alzheimer's disease, according to a new study by New York University School of Medicine scientists. The discovery solves a longstanding medical mystery involving descendants of a British woman who died in 1883 and may help lead to a better understanding of Alzheimer's and other dementias.
The NYU School of Medicine researchers found the genetic alteration, or mutation, in a gene they dubbed "BRI." The unusual mutation, which occurs at a "stop codon," produces an abnormal protein fragment that forms plaques in the brain of affected family members, according to the new study in June 24 issue of Nature. The researchers developed a blood test to detect the mutation.
"Our hope is that this genetic mutation, which causes a disease as devastating as Alzheimer's, will lead to a better understanding of how neurons are actually lost in the brain," says Jorge Ghiso, Ph.D., Associate Professor of Pathology at NYU School of Medicine, an author of the new study. "This is an important finding because it will give us another window onto the brain diseases associated with amyloid."
According to Creighton H. Phelps, Ph.D., Director of the Alzheimer's Disease Centers Program at the National Institute on Aging, "This exciting discovery provides new opportunities to uncover the cascade of events leading to the loss of synapses and neurons triggering the development of dementia. If we can interfere with this cascade, common to many of the dementias, including Alzheimer's, we may be able to stall the disease process in its tracks."
Amyloid is a general term used to describe proteins that form so-called beta-sheets, which fold in a particular way to form deposits in the brain. A number of brain disorders associated with dementia are linked to amyloid, including Alzheimer's, the most common form of senile dementia. While they all share a common fingerprint, namely the deposition of amyloid and neuronal loss, the nature and distribution of the amyloid protein within the brain differs with each disease for unknown reasons.
Although it hasn't been proven definitively, many researchers believe that amyloid deposition in the brain causes the death of nerve cells, especially in the areas of the brain vital to memory and learning.
One of the rare disorders associated with amyloid and dementia is found exclusively among the descendants of a British woman who died in 1883. So far, the disease has afflicted 38 of her descendants; altogether, her family tree comprises more than 300 individuals and spans over nine generations.
Based on the pattern in which members of this family have been afflicted with dementia, scientists knew that the disease was hereditary and autosomal dominant, meaning that only one copy of a mutated gene was needed to cause the disorder and that males and females were equally affected.
The advent of more sophisticated protein and DNA sequencing techniques as well as the availability of gene databanks allowed the researchers to identify the novel gene, which they subsequently mapped to chromosome 13.
The alphabet of DNA is composed of four chemicals, abbreviated TAGC, which are called bases. Sequences of three bases, for example TAG, comprise a codon; each codon spells out the message for a specific amino acid, which form proteins when strung together. The order of the amino acids determines which type of protein is formed. Thus, genes, which are long sequences of DNA, encode proteins.
"Using only fragments of a disease protein we obtained from an autopsy, we could almost pluck the gene encoding its precursor protein out of millions of DNA sequences posted in databanks," says Ruben Vidal, Ph.D., of NYU School of Medicine, one of the authors of the new study. "Ten years ago we couldn't have bagged the gene in this way," he says.
The disease afflicting the British family usually appears in middle age, around the age of 47, and is associated with some memory lapses. However, over the next decade, the affected person progressively develops severe dementia and spastic paralysis. In the late stages of the disease victims usually become quadriplegic and enter a vegetative state.
This particular form of dementia, which belongs to a group of mostly rare diseases called familial cerebral amyloid angiopathies, is associated with far more abundant amyloid deposition in the blood vessels of the brain than is typically seen in Alzheimer's disease, says Blas Frangione, M.D., Ph.D., Professor of Pathology at NYU School of Medicine, an author of the study. However, unlike Alzheimer's, the British disease is characterized by amyloid deposits in the cerebellum, which causes muscle spasms and other movement problems.
In both disorders, intracellular neurofibrillary tangles are present in affected neurons. The NYU group named the disease Familial British Dementia.
The NYU School of Medicine authors are Dr. Ruben Vidal, Dr. Blas Frangione, Dr. Agueda Rostagno and Dr. Jorge Ghiso. They analyzed bits of amyloid from an autopsy of a woman from the British family who developed the dementing brain disease at the age of 56, and died at 65. Dr. Gordon Plant, Dr. Tamas Révész and Dr. Simon Mead from the Institute of Neurology and the National Hospital for Neurology and Neurosurgery in London, who also are co-authors of the new study, performed the clinical studies and supplied the autopsy tissue and blood samples from family members. Dr. Plant has been studying the British family for many years and first met the NYU researchers in the late 1980s.
The researchers matched a series of amino acids from the amyloid to a sequence in a public databank on the World Wide Web. They were then able to use this sequence to find the gene. Public databanks contain hundreds of thousands of DNA sequences, one of the fruits of the government-sponsored project to sequence the entire human genome. Researchers worldwide deposit the DNA sequences in these databanks, which can be accessed via the Web.
Compared to the sequences reported in the databank, the NYU School of Medicine scientists found that the patient's DNA did not have a stop codon in the BRI gene, a message that marks the end of the reading frame for a particular protein, at a specific location. When they analyzed the DNA of the patient further, they found that in the stop codon TGA, the T was substituted for A, a kind of alteration called a base substitution or point mutation.
The mutation caused more amino acids to be added onto the protein. In fact, instead of a protein of 266 amino acids, the mutation caused a larger protein of 277 amino acids to be produced. The amyloid protein found deposited in the brain of patients with Familial British Dementia consists of the last 34 amino acids snipped from the larger protein.
The NYU group believes the precursor protein sticks out through the outer cell membrane and is cut by special enzymes, producing the amyloid fragment. The amyloid beta protein associated with Alzheimer's disease is generated by a similar mechanism; namely, a larger protein called amyloid precursor protein or APP sticks out from cell membranes and the amyloid fragment is formed by specific enzymatic degradation of this precursor protein. Due to the similarities between Alzheimer's disease and Familial British Dementia, the NYU School of Medicine group hopes that the discovery may shed light on the pathological mechanisms underlying Alzheimer's and other dementias.
Journal
Nature