Nucleic Acid Encoding a Brain Derived Tau Kinase Polypeptide and Methods of Use Thereof

Abstract

The present invention provides materials and methods for treating Alzheimer's disease and other tau related neurodegenerative disorders. A tau kinase, Brain Derived Tau Kinase (BDTK) is provided. BDTK can cause hyperphosphorylation of tau protein, which leads to formation of neurofibrillary tangles, which are implicated in the degenerative symptoms of Alzheimer's and other neurodegenerative disorders. Methods of diagnosis and treatment based on the discovery of this novel tau kinase are also provided.

1 . An isolated double-stranded nucleic acid molecule which upon denaturation, specifically hybridizes with SEQ ID NO: 1, said nucleic acid molecule comprising a sequence encoding a BDTK protein about 1321 amino acids in length, said encoded BDTK protein comprising an amino-terminal kinase domain. 
     
     
         2 - 5 . (canceled) 
     
     
         6 . A vector comprising the nucleic acid molecule of  claim 1 . 
     
     
         7 . A host cell comprising the vector of  claim 6 . 
     
     
         8 . The nucleic acid molecule of  claim 1 , wherein said nucleic acid encodes a BDTK protein comprising an amino acid sequence selected from the group consisting of an amino acid sequence of SEQ ID NO: 2 and natural allelic variants of said amino acid sequence. 
     
     
         9 . The nucleic acid molecule of  claim 8 , which comprises SEQ ID NO: 1. 
     
     
         10 . A nucleic acid molecule encoding an isolated fragment of the BDTK polypeptide of  claim 14 , wherein the fragment comprises an isolated BDTK kinase domain selected from the group consisting of SEQ ID NO:3 and SEQ ID NO:4. 
     
     
         11 . An isolated nucleic acid molecule
 encoding a kinase domain of the BDTK protein of  claim 14  having an amino acid sequence corresponding to amino acids 33-290 of SEQ ID NO: 2.   
     
     
         12 . An oligonucleotide between about 10 and about 200 nucleotides in length, which specifically hybridizes with the nucleic acid molecule of  claim 8 . 
     
     
         13 . (canceled) 
     
     
         14 . An isolated BDTK protein, said protein comprising an amino-terminal kinase domain which has tau kinase activity. 
     
     
         15 . The isolated protein of  claim 14  which is SEQ ID NO:2. 
     
     
         16 . An isolated fragment of the BDTK polypeptide of  claim 14 , wherein the fragment comprises an isolated BDTK kinase domain selected from the group consisting of SEQ ID NO:3 and SEQ ID NO:4. 
     
     
         17 . An antibody immunologically specific for the isolated protein of  claim 14 . 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . An antibody immunologically specific for the isolated kinase domain of  claim 16 . 
     
     
         21 . A pharmaceutical composition comprising a polypeptide as claimed in  claim 14  and a pharmaceutically acceptable carrier. 
     
     
         22 . A pharmaceutical composition comprising an antibody as claimed in  claim 17  and a pharmaceutically acceptable carrier. 
     
     
         23 . A method of diagnosing a neurodegenerative disorder in a patient, said disorder being characterized by an increase in tau phosphorylation, wherein said patient sample is analyzed by a method selected from the group consisting of:
 a) a method employing a specific binding member capable of binding to a BDTK nucleic acid sequence, the specific binding member comprising nucleic acid hybridizable with the BDTK sequence; and   b) a method of determining the presence, in a sample from a patient, of a polypeptide encoded by the BDTK nucleic acid and, if present, determining the expression level; and   c) a method wherein at least one antibody domain with specificity for an epitope selected from the group consisting of a native BDTK nucleic acid sequence epitope, or a polypeptide epitope, the specific binding member being labeled so that binding of the specific binding member to its binding partner is detectable; and   d) a method of PCR amplification involving one or more primers based on BDTK gene sequence to screen for an increase in BDTK expression in a sample from a patient; and   e) a method of determining the presence, in a sample from a patient, of a polypeptide encoded by the BDTK nucleic acid and, if present, determining the presence of mutations of the BDTK nucleic acid.   
     
     
         24 . (canceled) 
     
     
         25 . A method of identifying a target nucleic acid molecule in a test sample using a nucleic acid probe comprising at least 15 contiguous residues from the nucleic acid molecule of  claim 9 , the method comprising contacting the probe and the test sample under hybridizing conditions and observing whether hybridization takes place. 
     
     
         26 . A kit comprising a pair of the oligonucleotides of  claim 12 . 
     
     
         27 . A method of screening for substances which modulate the activity of the BDTK polypeptide of  claim 14 , the method comprising contacting at least one test substance with the BDTK polypeptide in a reaction medium, testing the activity of the treated BDTK polypeptide and comparing that activity with the activity of native, untreated BDTK polypeptide in a comparable reaction medium. 
     
     
         28 . (canceled) 
     
     
         29 . A chimeric animal comprising a nucleic acid molecule of  claim 1 .