Identification of compounds that disperse TDP-43 inclusions
Herein, methods of modulating inclusion formation and stress granules in cells are described. The methods comprise contacting a cell with an inclusion inhibitor. Methods for screening for modulators of TDP-43 aggregation are also described.
1. A method of modulating stress granules comprising contacting a cell with a TDP-43 inclusion inhibiting compound, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein stress granule formation is inhibited.
3. The method of claim 1 , wherein stress granule formation is disaggregated.
4. The method of claim 1 , wherein stress granule formation is stimulated.
5. The method of claim 1 , wherein the stress granule comprises tar DNA binding protein-43 (TDP-43), T-cell intracellular antigen 1 (TIA-1), TIA1 cytotoxic granule-associated RNA binding protein-like 1 (TIAR), GTPase activating protein binding protein 1 (G3BP-1), GTPase activating protein binding protein 2 (G3BP-2), tristetraprolin (TTP), fused in sarcoma (FUS), or fragile X mental retardation protein (FMRP).
6. The method of claim 1 , wherein the TDP-43 inclusion inhibiting compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the TDP-43 inclusion inhibiting compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 , wherein the method is performed in a subject suffering from a neurodegenerative disease or disorder, the method comprising administering the TDP-43 inclusion inhibiting compound to the subject.
9. The method of claim 8 , wherein the TDP-43 inclusion inhibiting compound inhibits stress granule formation or disaggregation.
10. The method of claim 8 , wherein the TDP-43 inclusion inhibiting compound increases stress granule formation or disaggregation.
11. The method of claim 8 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, frontotemporal dementia, FTLD-U (a frontotemporal dementia caused by mutations in progranulin protein), amyotrophic lateral sclerosis (ALS), Huntington's chorea, Creutzfeld-Jacob disease, trinucleotide repeat diseases, cerebral degenerative diseases presenile dementia, senile dementia, Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Huntington's disease (HD), Pick's disease, primary progressive aphasia, corticobasal dementia, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, Down's syndrome, multiple system atrophy, spinal muscular atrophy (SMA), spinocerebellar ataxia, spinal degenerative disease/motor neuron degenerative diseases, Hallervorden-Spatz syndrome, cerebral infarct, cerebral trauma, chronic traumatic encephalopathy, and transient ischemic attack, or any combination thereof.
12. The method of claim 8 , wherein the subject is a mammal.
13. The method of claim 12 , wherein the subject is a human.
14. The method of claim 8 , comprising further the step of diagnosing the subject for the neurodegenerative disease or disorder prior to the onset of said administration.
15. The method of claim 8 , wherein the pathology of said neurodegenerative disease or disorder comprises stress granules.