Animal models for demyelination disorders
This invention is in the field of neurology. Specifically, the invention relates to the discovery and characterization of molecular components that play a role in neuronal demyelination or remyelination. In addition, the invention relates to the generation of an animal model that exhibits hypomyelination. The compositions and methods embodied in the present invention are particularly useful for drug screening and/or treatment of demyelination disorders.
1. A method of reducing neuronal demyelination comprising administering to a myelinating cell an effective amount of a small molecule, wherein said small molecule reduces neuronal demyelination when administered to a transgenic mouse whose genome comprises:
(a) a stably integrated transgenic nucleotide sequence encoding interferon-gamma (IFN-γ) operably linked to an inducible promoter; and
(b) a heterozygous knock-out of the endogenous pancreatic endoplasmic reticulum (ER) kinase gene (PERK), wherein upon expression of said IFN-γ, said transgenic mouse exhibits a greater degree of demyelination relative to a transgenic mouse having a stably integrated transgenic nucleotide sequence encoding IFN-γ as in (a), but lacking said heterozygous knock-out of the PERK gene,
wherein said small molecule is characterized in that upon said administration and upon said expression of said IFN-γ in said transgenic mouse neuronal demyelination is reduced, and wherein said small molecule is effective to decrease growth and DNA damage protein 34 (GADD34) activity or increase pancreatic ER kinase (PERK) activity, resulting in an increase of phosphorylated eukaryotic translation initiation factor 2 alpha (p-eIF-2α) inside said myelinating cell.
2. The method of claim 1 , wherein said small molecule is effective to reduce a sustained stress level of endoplasmic reticulum (ER) in a myelinating cell.
3. The method of claim 1 , wherein said small molecule is an interferon-gamma (INF-γ) antagonist.
4. The method of claim 1 , wherein said small molecule is an interferon-gamma (INF-γ) agonist administered prior to the onset of neuronal demyelination to yield a prophylactic effect.
5. The method of claim 1 , wherein said myelinating cell is located in a subject's central nervous system or peripheral nervous system.
6. The method of claim 1 , wherein said myelinating cell is from a subject suffering from multiple sclerosis.
7. The method of claim 1 , wherein said myelinating cell is from a subject suffering from a neuronal demyelination inflicted by a pathogen or virus.
8. The method of claim of 1 , wherein said neuronal demyelination is inflicted by an inflammatory agent.
9. The method of claim 1 , wherein said small molecule is salubrinal.
10. The method of claim 1 , wherein said reduction of neuronal demyelination when said small molecule is administered to said transgenic mouse comprises a reduction in the loss of oligodendrocytes or Schwann cells in the nervous system of said mouse.
11. The method of claim 10 , wherein said reduction in the loss of oligodendrocytes or Schwann cells in the nervous system of said mouse when said small molecule is administered to said transgenic mouse is determined by characterizing a reduction in the level of an oligodendrocyte marker or a Schwann cell marker.
12. The method of claim 11 , wherein said oligodendrocyte marker is proteolipid protein (PLP).
13. The method of claim 1 , wherein said reduction of neuronal demyelination when said small molecule is administered to the transgenic mouse comprises an increase in myelinated axons in the nervous system of said mouse.
14. The method of claim 1 , wherein said small molecule inhibits protein phosphatase-1-growth and DNA damage protein 34 (PP1-GADD34) phosphatase activity in said myelinating cell.