Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1998-12-21
2001-06-19
Guzo, David (Department: 1636)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S194000, C435S320100, C435S455000, C435S070100, C435S325000, C435S366000, C536S023200
Reexamination Certificate
active
06248559
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a preventive or a therapeutic agent for Alzheimer's disease, a method of screening Alzheimer's disease and tau-protein kinase I which is originated from human being. More particularly, it relates to a preventive or a therapeutic agent for Alzheimer's disease using a tau-protein kinase I inhibitor; a method of screening a preventive or a therapeutic agent for Alzheimer's disease utilizing an amyloid beta-protein; a human-originated tau-protein kinase I which phosphorylates tau-protein, partial peptides thereof or peptides similar thereto; a gene which encodes the kinase; and a method of producing the same.
2. Description of Related Art
Alzheimer's disease is a progressive dementia which develops in late middle ages (45 to 65 years old) and its etiological changes are shrinkage of cerebral cortex due to a neuronal cell loss and degeneration of the neurons while, from the pathological view, many senile plaques and neurofibrillary tangles are noted in the brain. There is no pathologically substantial difference between the disease and senile dementia caused by the so-called natural aging which develops in the senile period of 65 years and older ages and, therefore, this is called senile dementia of Alzheimer type.
Numbers of the patients of this disease are increasing with an increase of population of aged people and disease is becoming serious in the society. There are various theories on the cause of this disease but, the cause has been still ambiguous and, accordingly, there has been a demand for prompt clarification.
It has been known that the quantities which appear in the two pathological changes which are characteristic to Arizheimer's disease and to senile dementia of Alzheimer type are well correlated with the degree of cognitive impairment. Accordingly, studies for clarifying the cause of those diseases by clarifying, in a molecular level, the accumulated insoluble substances resulting in those two pathological changes have been carried out since the first half of the 1980's.
It has been clarified already that a main component of the senile plaques which is one of those pathological changes is amyloid beta-protein (hereinafter, it may be abbreviated as “A&bgr;P”) [Annu. Rev. Neurosci., 12, 463-490 (1989)]. A neurofibrillary tangle which is another pathological change is due to an accumulation of a double-stranded fibrous substance called PHF (paired helical filament) in the neurons and, recently, the components thereof have been identified as ubiquitin and tau-protein which is one of the microtubule-associated proteins characteristic to brain [J. Biochem., 99, 1807-1810 (1986); Proc. Natl. Acad. Sci. USA, 83, 4913-4917 (1986)].
It is believed now that, in Alzheimer's disease, the amyloid beta-protein is extremely accumulated in the neurons and that, as a result of its correlation with the formation of PHF, death of the neurons is resulted.
It has been known that the tau-protein (hereinafter, the protein may be abbreviated as a “tau”) is usually a series of related proteins forming several bands at the molecular weights of 48-65 kd on SDS polyacrylamide gel electrophoresis and that it promotes the formation of microtubules.
It has been proved already by the use of polyclonal antibody to PHF [anti-ptau: J. Biolchem. 99, 1807-1810(1986)] and also of monoclonal antibody [tau-1 antibody; Proc. Natl. Acad. Asic. USA, 83, 4913-4917(1986)] that the tau which is incorporated in the PHF of the brain of Alzheimer's disease is extremely phosphorylated as compared with the normal one.
The present inventors have isolated an enzyme which catalyzes such an abnormal phosphorylation, named it “tau-protein kinase I” (hereinafter, it may be abbreviated as “TPK-I”) and clarified its biochemical properties [Seikagaku, vol. 64, no. 5, page 308 (1992)]. The inventors have further cloned the cDNA of rat TPK-I from the cDNA library of cerebral cortex of rats based upon the partial amino acid sequence of TPK-I, whereby the base sequence has been determined and the amino acid sequence has been proposed (Seq. ID No. 2 in the Sequence Listing; Japanese Patent Application 177241/92, FEBS Lett., 325, 167-172 (1993)).
As a result thereof, it has been confirmed that the primary structure of the rat TPK-I is identical with that of the enzyme which is known as a rat GSK-3&bgr; (glycogen syntase kinase 3&bgr;).[EMBO J., 9, 2431-2438 (1990)].
However, in finding the drugs which are effective for the prevention or the therapy of human diseases, the primary structure which are targets for the drug usually vary depending upon the animal species. Therefore, there are many cases that the interaction between the drug and the protein (in other words, sensitivity and effectiveness of the drug) greatly differs depending upon the animal species [e.g. Nature, 360, 161 (1992)]. Thus, in order to find drugs which are really effective to human being, it is desired that the investigation is carried out using proteins which are originated from human being. Particularly in the case of finding the drugs effective for the diseases which have not been found in animals other than human being such as Alzheimer's disease, it is believed to be essential to use proteins originated from human being. However, there has been no report on the separation and purification of TPK-I (or GSK-3&bgr;) from human tissues and, moreover, there has been no report on gene (cDNA) which encodes human TPK-I (or GSK-3&bgr;).
SUMMARY OF THE INVENTION
An object of the present invention is to clarify the correlation between the death of neurons and accumulation of PHF and amyloid beta-protein characteristically found in the brains of Alzheimer's disease and also to apply it to the clarification of the cause of Alzheimer's disease and further to the investigation to the preventive or therapeutic agents therefor.
Another object of the present invention is to clarify the structure of the human-originated TPK-I (which is essential for the progress of investigations for such drugs) on the molecular biological basis and to offer a method of producing it by means of gene technology.
The present inventors have carried out the investigations for achieving the above-given objects and confirmed that, when amyloid beta-protein acted to the neurons in the brain, activity of TPK-I significantly increases whereupon the extremely phosphorylated tau-protein found in PHF of the brains of Alzheimer's disease is resulted and, moreover, the neurons are killed, and that the above-mentioned increase in the TPK-I activity and neuronal cell death in the brain is inhibited by the treatment with the antisense oligonucleotide of the TPK-I.
In addition, with a view that the accumulation of PHF results in the degeneration of neurons in the brains of Alzheimer's disease and successively induces the death, the present inventors have for the first time cloned the gene (which encodes the human-originated TPK-I which is thought to be a key enzyme for the PHF formation) from the cDNA library of human fetus brain, whereupon its primary structure is determined and a method for constant supply (or production) of the human-originated TPK-I has been established.
The present invention has been achieved as a result of the above-given findings followed by further investigations, and its characteristic features are as follows:
(1) a preventive or a therapeutic agent for Alzheimer's disease, which comprises a substance exhibiting an inhibitory action to tau-protein kinase I as an effective component;
(2) a preventive or a therapeutic agent for Alzheimer's disease, which comprises an antisense oligonucleotide capable of hybridizing with mRNA or DNA of tau-protein kinase I as an effective component;
(3) a pharmaceutical composition for prevention or therapy of Alzheimer's disease, which comprises a substance exhibiting an inhibitory action to tau-protein kinase I
Hoshino Toshimitsu
Imahori Kazutomo
Saito Ken-Ichi
Sato Showbu
Shiratsuchi Akiko
Guzo David
Leffers, Jr. Gerald G.
Mitsubishi Chemical Corporation
Wenderoth , Lind & Ponack, L.L.P.
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