Transposon activation during aging and neuronal decline
The present invention relates to transposon activation and mobilization, particularly in the brain, during normal aging; reporter systems to detect such mobilization, along with cells and transgenic animals containing such systems; methods of monitoring neuronal function during normal aging; methods of determining the risk of age-related neuronal decline and age-related mortality; and the use of transposon inhibitors and apoptosis inhibitors to delay age-related neuronal decline and age-related mortality.
1. A method for determining if a test subject is at higher risk of accelerated age-related neuronal decline and in need of treatment of age-related neuronal decline, the method comprising
a. measuring expression of at least one retrotransposon in a biological sample from the test subject, and
b. determining whether the retrotransposon expression measured in step (a) exceeds expression of the retrotransposon in a control subject that is not afflicted with age-related neuronal decline,
wherein a higher level of retrotransposon expression in the test subject relative to the control subject indicates that the subject is at higher risk of accelerated age-related neuronal decline and is in need of treatment of age-related neuronal decline.
2. The method of claim 1 , wherein the subject is in need of treatment with a transposon inhibitor.
3. The method of claim 2 , wherein the transposon inhibitor is an inhibitor of a protein encoded by a transposon.
4. The method of claim 3 , wherein the protein encoded by the transposon is a transposase; an integrase; a reverse transcriptase; an endonuclease; a protein encoded by gag, pol, or env; an enzyme encoded by ORF1 of a non-LTR transposon; or an enzyme encoded by ORF2 of a non-LTR transposon.
5. The method of claim 2 , wherein the transposon inhibitor is an anti-retroviral drug; an inhibitor of reverse transcription; an inhibitor of transposase or integrase activity; an inhibitor of endonuclease activity; a zinc-finger that targets a transposon promoter region; a repressor that inhibits a transposon; an innate antiretroviral resistance factor; a small interfering RNAs (siRNA), short hairpin RNA (shRNA), morpholino, or antisense oligonucleotide directed to a TE transcript; or an inhibitor of post-translational processing or proteolysis of a transposon-encoded protein.
6. The method of claim 1 , wherein the retrotransposon includes a gypsy element.
7. The method of claim 1 , further comprising administering to the subject an effective amount of a transposon inhibitor.
8. The method of claim 7 , wherein the transposon inhibitor is an inhibitor of a protein encoded by a transposon.
9. The method of claim 8 , wherein the protein encoded by the transposon is a transposase; an integrase; a reverse transcriptase; an endonuclease; a protein encoded by gag, pol, or env; an enzyme encoded by ORF1 of a non-LTR transposon; or an enzyme encoded by ORF2 of a non-LTR transposon.
10. The method of claim 1 , wherein the biological sample in step (a) is contacted with an antibody against a transposon protein.
11. The method of claim 1 , wherein the retrotransposon is an LTR retrotransposon.
12. The method of claim 7 , wherein the transposon inhibitor is an anti-retroviral drug; an inhibitor of reverse transcription; an inhibitor of transposase or integrase activity; an inhibitor of endonuclease activity; a zinc-finger that targets a transposon promoter region; a repressor that inhibits a transposon; an innate antiretroviral resistance factor; a small interfering RNAs (siRNA), short hairpin RNA (shRNA), morpholino, or antisense oligonucleotide directed to a TE transcript; or an inhibitor of post-translational processing or proteolysis of a transposon-encoded protein.
13. The method of claim 2 , wherein the transposon inhibitor is an inhibitor of reverse transcriptase activity.
14. The method of claim 2 , wherein the transposon inhibitor is an inhibitor of endonuclease activity.
15. The method of claim 2 , wherein the transposon inhibitor is an inhibitor of integrase activity.
16. The method of claim 2 , wherein the transposon inhibitor is an anti-retroviral drug.
17. The method of claim 7 , wherein the transposon inhibitor is an inhibitor of reverse transcriptase activity.
18. The method of claim 7 , wherein the transposon inhibitor is an inhibitor of endonuclease activity.
19. The method of claim 7 , wherein the transposon inhibitor is an inhibitor of integrase activity.
20. The method of claim 7 , wherein the transposon inhibitor is an anti-retroviral drug.