Compositions and methods related to tauopathy
Disclosed herein are isolated polypeptides, antibody preparations, treatment methods, diagnostic methods, and screening methods related to tauopathy. Generally, the isolated polypeptide includes a core pentapeptide, with the proviso that the isolated polypeptide is not a native full-length tau protein. Generally, the antibody preparations include antibody that specifically binds to SEQ ID NO:12. Generally, the treatment methods include administering to a subject a composition that includes the isolated polypeptide. Generally, the diagnostic methods includes contacting a sample from a subject with an antibody preparation that includes antibody that specifically binds to SEQ ID NO:12, and then detecting a ligand in the sample that specifically binds the antibody preparation. Generally, the screening method includes incubating a mixture of caspase-2, a labeled caspase-2 cleavage substrate, and a test compound under conditions effective to permit the caspase-2 to cleave the caspase-2 cleavage substrate, then determining whether the test compound inhibits cleavage of the substrate by caspase-2.
1. An isolated polypeptide comprising a core pentapeptide sequence having the formula aa 5 -aa 4 -aa 3 -aa 2 -aa 1 , wherein:
aa 5 is tyrosine or phenylalanine;
aa 4 is lysine, aspartic acid, serine, or cysteine;
aa 3 is proline or valine;
aa 2 is valine, phenylalanine, alanine, or tyrosine; and
aa 1 is aspartic acid;
with the proviso that the isolated polypeptide is not a native full-length tau protein;
the N-terminal amino acid of the polypeptide is modified to comprise a methyl group or a benzyl group; and
the C-terminal amino acid of the polypeptide is modified to comprise an aldehyde.
2. The isolated polypeptide of claim 1 further comprising at least one amino acid appended to the N-terminus of the core pentapeptide.
3. The isolated polypeptide of claim 2 further comprising at least one amino acid appended to the C-terminus of core pentapeptide.
4. The isolated polypeptide of claim 1 further comprising at least one amino acid appended to the C-terminus of core pentapeptide.
5. The isolated polypeptide of claim 1 wherein the core pentapeptide is SEQ ID NO:1.
6. The isolated polypeptide of claim 1 wherein the core pentapeptide is one of SEQ ID NO:20-34.
7. The isolated polypeptide of claim 1 further comprising a chemical group that is covalently or noncovalently reactive with a cysteine residue at the active site of caspase-2.
8. The isolated polypeptide of claim 1 further comprising a prodrug modification.
9. A composition comprising:
the isolated polypeptide of claim 1 ; and
a pharmaceutically acceptable carrier.
10. The composition of claim 9 wherein the isolated polypeptide further comprises a chemical group that is covalently or noncovalently reactive with a cysteine residue at the active site of caspase-2.
11. The composition of claim 9 further comprising at least one amino acid appended to the N-terminus of the core pentapeptide.
12. The composition of claim 9 further comprising at least one amino acid appended to the C-terminus of core pentapeptide.
13. The composition of claim 9 further comprising at least one amino acid appended to the C-terminus of core pentapeptide.
14. The composition of claim 9 wherein the core pentapeptide is SEQ ID NO:1.
15. The composition of claim 9 wherein the core pentapeptide is one of SEQ ID NO:20-34.
16. The composition of claim 9 further comprising a prodrug modification.