METHOD FOR TREATMENT OF DEGENERATIVE BRAIN DISORDERS COMPRISING INHIBITOR OF SUM01 AND BACE1 INTERACTION AS AN ACTIVE INGREDIENT

20140186357

14/021210

September 09, 2013

A treatment method for degenerative brain disorders using a pharmaceutically effective dose of the inhibitor of SUMO1 (small ubiquitin-like modifier 1) and BACE1 (β-secretase) interaction, or the inhibitor of SUMO1 expression or activation is provided. More specifically, it was confirmed that SUMO1 increased BACE1 accumulation and Aβ generation, that is SUMO1 regulated BACE1 accumulation by interacting with BACE1, and BACE1 dileucine motif was involved in SUMO1-mediated BACE1 accumulation. In addition, SUMO1 protein induced autophagy in H4 cells, while SUMO1 depletion reduced LC3-II level. It was further confirmed that SUMO1 and LC3 were co-localized in the cortex of APP transgenic mice. As shown herein, a pharmaceutically effective dose of the inhibitor of SUMO1 and BACE1 interaction or the inhibitor of SUMO1 expression can be effectively used for the treatment of degenerative brain disorders.

KOREA CENTER FOR DISEASE CONTROL AND PREVENTION (CHUNGCHEONGBUK-DO, KR)

1. A treatment method for degenerative brain disorders containing the step of administering a pharmaceutically effective dose of the inhibitor of SUMO1 (small ubiquitin-like modifier 1) and BACE1 (β-secretase) interaction or the inhibitor of SUMO1 expression or activation to a subject having degenerative brain disorders.

2. The treatment method for degenerative brain disorders according to claim 1, wherein the SUMO1 is composed of the amino acid sequence represented by SEQ. ID. NO: 1.

3. The treatment method for degenerative brain disorders according to claim 1, wherein the full length BACE1 is composed of the amino acid sequence represented by SEQ. ID. NO: 2, or the C-terminal deleted sequence from the original BACE1 sequence represented by SEQ. ID. NO: 4.

4. The treatment method for degenerative brain disorders according to claim 1, wherein the inhibitor of SUMO1 and BACE interaction is selected from the group consisting of peptides binding complementarily to SUMO1 or BACE1, peptides binding complementarily to the fragment having C-terminal deleted from the BACE1 sequence represented by SEQ. ID. NO: 3, peptide mimetics, substrate analogs, aptamers and antibodies.

5. The treatment method for degenerative brain disorders according to claim 1, wherein the inhibitor of SUMO1 expression or activation is selected from the group consisting of antisense nucleotide binding complementarily to SUMO1 mRNA, siRNA, and shRNA.

6. The treatment method for degenerative brain disorders according to claim 1, wherein the inhibitor of SUMO1 expression or activation is selected from the group consisting of peptides binding complementarily to SUMO1 protein, peptide mimetics, substrate analogs, aptamers and antibodies.

7. The treatment method for degenerative brain disorders according to claim 1, wherein the degenerative brain disorders is selected from the group consisting of dementia, Alzheimer's, stroke, Huntington's disease, Pick's disease, and Creutzfeldt-Jakob disease.

8. A diagnostic method for degenerative brain disorders comprising the following steps: 1) measuring the level of SUMO1 and BACE1 interaction or the level of SUMO1 expression in a sample separated from a test subject; 2) selecting a subject demonstrating the increased level of SUMO1 and BACE1 interaction or the increased level of SUMO1 expression, measured in step 1), compared with that of the normal control; and 3) evaluating the risk of degenerative brain disorders in the selected subject of step 2).

9. The diagnostic method for degenerative brain disorders according to claim 8, wherein the sample is selected from the group consisting of serum, plasma, and blood.

10. The diagnostic method for degenerative brain disorders according to claim 8, wherein the measurement of the level of SUMO1 and BACE1 interaction is performed by the method selected from the group consisting of immunofluorescence method, mass spectrometry, protein chip assay, Western blotting, and ELISA.

11. The diagnostic method for degenerative brain disorders according to claim 8, wherein the measurement of the level of SUMO1 expression is performed by the method selected from the group consisting of RT-PCR, DNA chip assay, immunofluorescence method, Western blotting, and ELISA.

12. The diagnostic method for degenerative brain disorders according to claim 8, wherein the degenerative brain disorders is selected from the group consisting of dementia, Alzheimer's, stroke, Huntington's disease, Pick's disease, and Creutzfeldt-Jakob disease.

13. A screening method for candidates for treating degenerative brain disorders comprising the following steps: 1) treating a test material to the cells expressing SUMO1 and BACE1; 2) measuring the level of SUMO1 and BACE1 interaction or the level of SUMO1 expression in the cells of step 1); and 3) selecting a test material that was able to reduce the level of SUMO1 and BACE1 interaction or the level of SUMO1 expression, measured in step 2), compared with the non-treated control.

14. The screening method for candidates for treating degenerative brain disorders according to claim 13, wherein the measurement of the level of SUMO1 and BACE1 interaction is performed by the method selected from the group consisting of immunofluorescence method, mass spectrometry, protein chip assay, Western blotting, and ELISA.

15. The screening method for candidates for treating degenerative brain disorders according to claim 13, wherein the measurement of the level of SUMO1 expression is performed by the method selected from the group consisting of RT-PCR, DNA chip assay, immunofluorescence method, Western blotting, and ELISA.

16. The screening method for candidates for treating degenerative brain disorders according to claim 13, wherein the degenerative brain disorders is selected from the group consisting of dementia, Alzheimer's, stroke, Huntington's disease, Pick's disease, and Creutzfeldt-Jakob disease.

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edspap.20140186357