Claims
- 1. A method of diagnosing a tauopathy comprising the steps of:
(a) obtaining a sample from a subject; (b) determining the ratio of a four-repeat tau isomer to a three-repeat tau isomer in a cell of said sample, wherein an increase in said ratio, as compared to a comparable normal cell, indicates that said subject is afflicted with a tauopathy.
- 2. The method of claim 1, wherein said tauopathy is a Fronto-Temporal Dementia.
- 3. The method of claim 1, wherein said tauopathy is Familial Multiple System Tauopathy, Pick's Disease, Progressive Supranuclear Palsy, Corticobasal Degeneration, Familial Gerstmann-Straussler-Scheinker Disease or Alzheimer's Disease.
- 4. The method of claim 1, wherein said sample is cerebrospinal fluid or a brain biopsy.
- 5. The method of claim 1, further comprising determining said ratio in a comparable normal cell.
- 6. The method of claim 1, wherein said determining comprises measuring the protein level of said four-repeat tau isomer.
- 7. The method of claim 6, further comprising measuring the protein level of said three-repeat tau isomer.
- 8. The method of claim 6, wherein said measuring comprises contacting said sample with a tau binding protein.
- 9. The method of claim 8, wherein said tau binding protein is a tau antibody.
- 10. The method of claim 9, wherein said tau antibody is used in a Western blot, an ELISA or an RIA.
- 11. The method of claim 1, wherein said determining comprises detecting a tau mutation in the nucleic acid of said cell.
- 12. The method of claim 11, wherein said detecting comprises PCR.
- 13. The method of claim 12, further comprising the step of reverse transcription.
- 14. The method of claim 12, further comprising southern blotting.
- 15. The method of claim 11, wherein said mutation is an intronic mutation.
- 16. The method of claim 11, wherein said mutation is an exonic mutation.
- 17. The method of claim 16, wherein said mutation affects phosphorylation of a tau isomer.
- 18. The method of claim 11, wherein said mutation is a splice mutation.
- 19. The method of claim 17, wherein said mutation is a G to A transition in the nucleotide immediately 3′ of the exon 10 splice-donor site.
- 20. The method of claim 16, wherein said mutation is in codon 301 in exon 10 of tau.
- 21. A transgenic, non-human animal, cells of which express an increased ratio of four-repeat tau isomer to three-repeat tau isomer due to a mutation in the tau gene.
- 22. The animal of claim 21, wherein said animal is a mouse, rat, sheep, cow, or rabbit.
- 23. The animal of claim 21, wherein said increased ratio is the result of a splice mutation in the tau gene.
- 24. The animal of claim 24, wherein said mutation is a G to A transition in the nucleotide immediately 3′ of the exon 10 splice-donor site.
- 25. A method for screening a candidate substance for activity against tau filament formation comprising:
(a) providing a cell which expresses a four-repeat tau isomer and a three-repeat tau isomer; (b) contacting said cell with said candidate substance; and (c) determining an alteration on the four-repeat tau isomer to three-repeat tau isomer ratio in said cell.
- 26. The method of claim 25, wherein the candidate substance is a polynucleotide, a polypeptide, a small molecule inhibitor.
- 27. The method of claim 26, wherein said polynucleotide encodes, or said polypeptide is, an enzyme, an antibody, or a transcription factor.
- 28. The method of claim 25, further comprising determining said ratio in a comparable normal cell.
- 29. The method of claim 25, wherein said determining comprises measuring the protein level of said four-repeat tau isomer.
- 30. The method of claim 29, further comprising measuring the protein level of said three-repeat tau isomer.
- 31. The method of claim 29, wherein said measuring comprises contacting said sample with a tau binding protein.
- 32. The method of claim 31, wherein said tau binding protein is a tau antibody.
- 33. The method of claim 32, wherein said tau antibody is used in a Western blot, an ELISA or an RIA.
- 34. The method of claim 25, wherein said cell is a CNS-derived cell.
- 35. A method for treating a subject afflicted with a tauopathy characterized by a elevated ratio of four-repeat tau isomer to three-repeat tau isomer comprising providing to said subject a composition that decreases said ratio.
- 36. The method of claim 35, wherein said composition increases the relative amount of said three-repeat isomer.
- 37. The method of claim 35, wherein said composition decreases the relative amount of said four-repeat isomer.
- 38. The method of claim 35, wherein the candidate substance is a polynucleotide, a polypeptide, or a small molecule inhibitor.
- 39. The method of claim 35, wherein said polynucleotide encodes, or said polypeptide is, an enzyme, an antibody, or a transcription factor.
- 40. The method of claim 35, wherein the polynucleotide is an expression construct comprising a promoter active in eukaryotic cells.
- 41. The method of claim 40, wherein the expression construct is a viral expression construct.
- 42. The method of claim 41, wherein the viral expression construct is retrovirus, adenovirus, adeno-associated virus, herpesvirus, or vaccina virus.
- 43. The method of claim 40, wherein the polynucleotide encodes an enzyme, an antibody, or a transcription factor.
- 44. The method of claim 35, further comprising providing to said subject an agent for the treatment of a cognitive disorder selected from the group consisting of a cerebral vasodilator, a cerebral metabolic enhancer, a nootropic agent, a psychostimulant, a neuropeptide, an adrenergic agent, a dopaminergic agent, a gabaminergic agent a serotinergic agent, an acetylcholine-related agent, a synaptic enhancer, and a cholinergic agonist.
- 45. The method of claim 35, wherein said subject is a human.
- 46. The method of claim 35, wherein said tauopathy is Familial Multiple System Tauopathy, Pick's Disease, Progressive Supranuclear Palsy, Corticobasal Degeneration, Familial Gerstmann-Straussler-Scheinker Disease or Alzheimer's Disease.
Government Interests
[0001] The government may own rights in the present invention pursuant to grant numbers AG10133 and NS14426 from the National Institutes of Health/National Institute on Aging and National Institutes of Health/National Institute of Neurologic Disorders and Stroke, respectively.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60087557 |
Jun 1998 |
US |
Continuations (1)
|
Number |
Date |
Country |
Parent |
PCT/US99/12036 |
May 1999 |
US |
Child |
09726771 |
Nov 2000 |
US |