Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1997-08-08
1999-11-16
LeGuyader, John L.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 691, 4352542, 43525421, 4353201, 435325, 435366, 435372, 536 235, C12Q 168, C12N 1581, C12N 1585, C07A 2104
Patent
active
059855649
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
It has been appreciated for some time that Alzheimer's Disease has a complex etiology. At least 15 percent of the cases appear to be due to the inheritance of an autosomal-dominant mutation, but the majority are "sporadic", showing no clear association with any identifiable genetic or environmental factor. Feldman, R. G., et al., Neurology, 13:811-824 1963; Heston, L. L., et al., Arch Gen. Psychiat., 38:1084-1090 (1981); Terry, R. D., Aging, 7:11-14 (1978); Jarvik, L. F. and Matsuyama, S. S., "The Biological Substrates of Alzheimer's Disease", Academic Press, pp. 17-20 (1986). Even identical twins can show a large discordance in the age of onset of the disease. Nee, L. E., et al., Neurology, 37:359-363 (1987). Yet despite this variation, Alzheimer's Disease shows a uniform set of clinical and pathological features--progressive loss of memory and other intellectual functions beginning in middle to late life, coupled with neuronal cell loss in the higher centers of the brain. Price, D. L., Ann. Rev. Neurosci., 9:489-512 (1986).
While much has been learned about the biochemistry and expression of the aberrant protein deposits that characterize Alzheimer's Disease, progress toward the development of methods for the diagnosis and treatment of the disease has been slow. This is due, at least in part, to the fact that the molecular basis for the disease pathology has remained obscure.
SUMMARY OF THE INVENTION
The present invention relates to a method of identifying genes which encode gene products (e.g. proteins and RNA) which cause chromosome missegregation, genes identified by the method, proteins encoded by the genes, antibodies which bind the gene product, a method of identifying agents which reduce (partially or totally) chromosome missegregation in cells, constructs useful in the method of identifying agents which reduce chromosome missegregation in cells, agents identified by the method, methods of preventing chromosome missegregation in cells and agents (including antibodies, peptides, antisense and complementary oligonucleotides and small organic molecules) useful in preventing chromosome missegregation. Also included are genes which hybridize to polynucleotides whose sequences are disclosed herein and which encode proteins which cause chromosome missegregation. As described herein, Applicant has shown that the incidence of trisomy 21 is higher in fibroblasts from individuals with Alzheimer's Disease than in fibroblasts from individuals without Alzheimer's Disease. Based in part on this result, Alzheimer's Disease arises from an accumulation of trisomy 21 cells during the life of the individual, resulting from chromosomal missegregation.
The present invention relates to an assay useful to identify genes whose expression causes chromosome missegregation. Twenty-two genes whose products promoted chromosome missegregation in the yeast assay were isolated from cells obtained from an individual with Alzheimer's Disease. These results provide evidence that genes which give rise to gene products which cause improper chromosome segregation play a role in causing Alzheimer's Disease by promoting the accumulation of trisomy 21 cells. Agents which reduce improper chromosome segregation will slow or inhibit the progression of Alzheimer's Disease.
One embodiment of the present invention is a method of detecting a gene which encodes a gene product which causes chromosome missegregation, thereby resulting in a disease condition. As a result of chromosome missegregation, total chromosome number in the progeny may be greater than, less than or the same as the number of chromosomes in cells in which missegregation does not occur. "Chromosome missegregation" includes processes which result in aneuploid cells, which include cells with an abnormal number of chromosomes. Aneuploid cells include hyperploid cells, which are cells with a greater than normal number of chromosomes, or hypoploid cells, which are cells with a lower than normal number of chromosomes. "Chromosome missegregation" also in
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Li Jinhe
Potter Huntington
LeGuyader John L.
President and Fellows of Harvard College
Shibuya Mark L.
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