Luteolin for treatment of neuromuscular movement disorder
Methods for modification of abnormal protein interactions manifested as excessive PACT-mediated PKR activation within cells are described. Methods include administration of luteolin to cells that exhibit dysregulation in PACT-mediated PKR activation. Methods can decrease or prevent excessive non-viral PACT-mediated PKR activation in a cell as may occur due to expression by the cell of a mutant PACT protein. Methods can decrease an abnormal prolonged stress response as may occur in the absence of a stress-inducing activity or agent.
1. A method for disrupting PACT-mediated PKR activation in a cell, comprising:
administering luteolin the cell; wherein,
the cell exhibits a dysregulation in PACT-mediated PKR activation; and wherein,
following the administration, an interaction between PACT protein expressed by the cell and PKR protein expressed by the cell is decreased as compared to the interaction prior to the administration.
2. The method of claim 1 , further comprising determining a concentration or rate of formation of a PACT-PKR heterodimer prior to and following the administration, wherein the interaction decrease is indicated by a decrease in the PACT-PKR heterodimer concentration or rate of formation following the administration.
3. The method of claim 1 , further comprising determining a concentration or rate of formation of a PACT-PACT homodimer prior to and following the administration, wherein the interaction decrease is indicated by a decrease in PACT-PACT homodimer concentration or rate of formation following the administration.
4. The method of claim 1 , further comprising determining a concentration or rate of formation of a PACT-TBRP heterodimer prior to and following the administration, wherein the interaction decrease is indicated by an increase in PACT-TBRP heterodimer concentration or rate of formation following the administration.
5. The method of claim 1 , wherein the PACT protein expressed by the cell comprises a mutation.
6. The method of claim 5 , wherein the mutation comprises one or more of a cysteine to serine mutation, a cysteine to phenylalanine mutation, a cysteine to arginine mutation, a proline to leucine mutation, threonine to serine mutation, and an asparagine to serine mutation.
7. The method of claim 5 , wherein the mutation comprises one or more of T34S, N102S, C77S, C213F, C213R, and P222L.
8. The method of claim 1 , wherein the luteolin is administered to the cell such that the luteolin contacts the cell at a concentration of from about 10 μM to about 100 μM.
9. A method for decreasing an abnormal integrated stress response in a cell, the method comprising:
determining a first expression or activity level of a stress biomarker expressed in response to the abnormal stress response;
following the determination, administering luteolin the cell; and
following the administration, determining a second expression or activity level of the stress biomarker; wherein
the second expression or activity level is within about 10% of a normal, non-stress expression or activity level for the biomarker in the cell.
10. The method of claim 9 , wherein the cell expresses a mutated PACT protein.
11. The method of claim 10 , wherein the mutation comprises one or more of a cysteine to serine mutation, a cysteine to phenylalanine mutation, a cysteine to arginine mutation, a proline to leucine mutation, threonine to serine mutation, and an asparagine to serine mutation.
12. The method of claim 9 , wherein the biomarker comprises an endoplasmic reticulum stress biomarker.
13. The method of claim 12 , wherein the endoplasmic reticulum stress biomarker comprises accumulation of misfolded proteins in an endoplasmic reticulum of the cell, anti-cleaved PARP1 antibody, anti-β-actin antibody, binding immunoglobulin protein, phosphorylated Inositol Requiring 1 protein, phosphorylated PKR-like ER kinase, C/EBP homologous protein.
14. The method of claim 9 , wherein the biomarker comprises an oxidative stress biomarker.
15. A method for treating a dysregulation in PACT-mediated PKR activation in a subject, the method comprising administering to the subject a composition comprising a therapeutically effective amount of luteolin.
16. The method of claim 15 , wherein the subject has been diagnosed with a dystonia.
17. The method of claim 16 , wherein the dystonia is a congenital dystonia or an induced dystonia.
18. The method of claim 16 , wherein the dystonia is dystonia 16.
19. The method of claim 15 , wherein the subject has been diagnosed with Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, prion disease, or Down's Syndrome.