Neurodegenerative diseases and methods of modeling

Abstract

Disclosed are embryonic stem cells and motor neurons derived from mice carrying transgenic alleles of the normal or mutant human SOD1 gene. Also disclosed are in vitro systems employing such SOD1 transgenic motor neurons for the study of neural degenerative disease.

1 - 14 . (canceled) 
     
     
         15 . A method of identifying an agent that affects the survival of a mutant motor neuron comprising:
 providing a mutant motor neuron comprising a SOD1 mutant allele;   providing a test agent;   contacting the mutant motor neuron with the test agent; and   determining the effect of the test agent on survival of the mutant motor neuron by comparing the survival of the mutant motor neuron to the survival of a control motor neuron lacking the SOD1 mutant allele, which control motor neuron is contacted with the test agent for a period of time and under conditions identical to that of the SOD1 mutant motor neuron.   
     
     
         16 . The method of  claim 15 , wherein the SOD1 mutant motor neuron comprises a mutation associated with a neurodegenerative disease. 
     
     
         17 . The method of  claim 15 , wherein the control motor neuron is wild type. 
     
     
         18 . The method of  claim 15 , wherein the test agent comprises an agent selected from the group consisting of: a cell, a small molecule, a hormone, a vitamin, a nucleic acid molecule, an enzyme, an antibody, an amino acid, a virus, and combinations thereof. 
     
     
         19 . The method of  claim 15 , further comprising providing a glial cell, which glial cell negatively affects survival of the mutant motor neuron. 
     
     
         20 . The method of  claim 19 , wherein the glial cell comprises a SOD1 mutant allele. 
     
     
         21 . The method of  claim 20 , wherein the SOD1 mutant allele of the glial cells is transgenic. 
     
     
         22 . The method of  claim 20 , wherein the SOD1 mutant allele of the glial cell comprises a mutation associated with amyotrophic lateral sclerosis. 
     
     
         23 . The method of  claim 22 , wherein the SOD1 mutant allele of the glial cell comprises a glycine to alanine substitution at amino acid position 93. 
     
     
         24 - 75 . (canceled) 
     
     
         76 . A method of promoting the survival of a motor neuron, the method comprising contacting the motor neuron with an agent that inhibits the expression or activity of a gene or a product of a gene in Table 2. 
     
     
         77 . The method of  claim 76 , wherein the gene in Table 2 is a gene involved in inflammation. 
     
     
         78 . The method of  claim 76 , wherein the agent inhibits the expression or activity of a prostaglandin D receptor. 
     
     
         79 . The method of  claim 76 , wherein the motor neuron is contacted with the agent in vitro. 
     
     
         80 . The method of  claim 76 , wherein the motor neuron is contacted with the agent in vivo. 
     
     
         81 . The method of  claim 78 , wherein the agent is selected from the group consisting of a cell, a small molecule, a hormone, a vitamin, a nucleic acid molecule, an enzyme, an antibody, an amino acid, a virus, and combinations thereof. 
     
     
         82 . The method of  claim 78 , wherein the agent is a small molecule. 
     
     
         83 . The method of  claim 78 , wherein the agent is MK-0542. 
     
     
         84 . A method of mediating motor neuron microglial toxicity, the method comprising contacting the motor neuron with an agent that reduces the expression or activity of a prostaglandin D2 (PGD2) receptor and thereby mediate motor neuron microglial toxicity. 
     
     
         85 . The method of  claim 84 , wherein the motor neuron is contacted with the agent in vitro. 
     
     
         86 . The method of  claim 84 , wherein the motor neuron is contacted with the agent in vivo. 
     
     
         87 . The method of  claim 84 , wherein the agent is selected from the group consisting of a cell, a small molecule, a hormone, a vitamin, a nucleic acid molecule, an enzyme, an antibody, an amino acid, a virus, and combinations thereof. 
     
     
         88 . The method of  claim 84 , wherein the agent is a small molecule. 
     
     
         89 . The method of  claim 84 , wherein the agent is MK-0542.