Sirtuin related therapeutics and diagnostics for neurodegenerative diseases
Provided herein are methods and compositions for modulating the activity of sirtuin deacetylase protein family members; p53 activity; apoptosis; lifespan and sensitivity to stress of cells and organisms. Exemplary methods comprise contacting a cell with an activating compound, such as a flavone, stilbene, flavanone, isoflavone, catechin, chalcone, tannin or anthocyanidin; or an inhibitory compound, such as a sphingolipid, e.g., sphingosine. Also disclosed herein are methods for treating, preventing or diagnosing a disease associated with neuronal cell death, e.g., a neurodegenerative disease.
1 . A method for treating or preventing a neurodegenerative disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an agent that increases the activity or protein level of a sirtuin in a cell.
2 . The method of claim 1 , wherein the sirtuin is SIRT1.
3 . The method of claim 2 , wherein the agent is a nucleic acid encoding SIRT1.
4 . The method of claim 1 , wherein the agent is a sirtuin-activating compound, salt or prodrug thereof.
5 . The method of claim 4 , wherein the sirtuin-activating compound comprises the formula selected from the group consisting of formulas 1-25, 30 and 32-65.
6 . The method of claim 1 , wherein the subject is human.
7 . The method of claim 1 , wherein the neurodegenerative disease is a disease selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, and multiple sclerosis.
8 . The method of claim 1 , further comprising administering to the subject a therapeutically effective amount of a therapeutic agent for treating the neurodegenerative disease.
9 . The method of claim 1 , wherein the subject is a subject who has been diagnosed with a neurodegenerative disease.
10 . The method of claim 9 , wherein the diagnosis comprises determining the level or activity of a sirtuin in the subject.
11 . The method of claim 10 , wherein the neurodegenerative disease is Alzheimer's disease and the diagnosis comprises determining the level or activity of SIRT1 in a brain sample of the subject.
12 . The method of claim 10 , wherein the neurodegenerative disease is ALS and the diagnosis comprises determining the level or activity of SIRT1 in a spinal cord sample of the subject.
13 . The method of claim 1 , further comprising monitoring the progression of the neurodegenerative disease.
14 . The method of claim 13 , wherein monitoring the progression of the neurodegenerative disease comprises determining the level or activity of a sirtuin in the subject.
15 . The method of claim 14 , wherein the neurodegenerative disease is Alzheimer's disease and monitoring the progression of the disease comprises determining the level or activity of SIRT1 in a brain sample of the subject.
16 . The method of claim 14 , wherein the neurodegenerative disease is ALS and monitoring the progression of the disease comprises determining the level or activity of SIRT1 in a spinal cord sample of the subject.
17 . A method for determining whether a subject has or is likely to develop a neurodegenerative disease, comprising (i) obtaining a biological sample from a subject; and (ii) determining the level or activity of a sirtuin in the biological sample, wherein a higher level or activity of the sirtuin the biological sample of the subject relative to a control level indicates that the subject has or is likely to develop a neurodegenerative disease.
18 . The method of claim 17 , wherein the sirtuin is SIRT1.
19 . The method of claim 18 , wherein the biological sample is a brain sample.
20 . The method of claim 19 , wherein the disease is Alzheimer's disease.
21 . The method of claim 18 , wherein the disease is ALS and the biological sample is a spinal cord sample.
22 . A method for treating or preventing a neurodegenerative disease in a subject, comprising determining whether a subject has or is likely to develop a neurodegenerative disease according to the method of claim 17 and administering to a subject who has been diagnosed as having or as being likely to develop a neurodegenerative disease a therapeutically effective amount of a therapeutic agent for treating the neurodegenerative disease.
23 . A composition comprising a compound having a formula selected from the group of formulas 1-25, 30 and 32-65 and a therapeutic agent for treating a neurodegenerative disease.