Methods for treating 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 therapeutic small molecule identified by a method comprising:
a) administering a candidate small molecule to a transgenic mouse whose genome comprises:
(i) a stably integrated transgenic nucleotide sequence encoding interferon-gamma (IFN-γ) operably linked to an inducible promoter; and
(ii) a heterozygous knock-out of the endogenous pancreatic endoplasmic reticulum (ER) kinase gene (PERK); and
b) identifying said candidate small molecule as a therapeutic small molecule when upon expression of said IFN-γ, said transgenic mouse exhibits a decreased 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 not administered said candidate small molecule.
2. The method of claim 1 , wherein said therapeutic 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 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.
4. The method of claim 3 , 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.
5. The method of claim 4 , wherein said oligodendrocyte marker is proteolipid protein (PLP).
6. The method of claim 1 , wherein said reduction of neuronal demyelination when said small molecule is administered to said transgenic mouse comprises an increase in myelinated axons in the nervous system of said mouse.
7. The method of claim 1 , 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.
8. The method of claim 7 , wherein said small molecule inhibits protein phosphatase-1-growth and DNA damage protein 34 (PP1-GADD34) phosphatase activity in said myelinating cell.