Methods for the detection, treatment, and prevention of neurodegeneration

Abstract

In general, the invention provides methods for identifying genes involved in neurodegeneration and therapeutics for treating animals with a neurodegenerative disease. Methods and kits for the detection of compounds which enhance neuroprotection and diagnostic kits for the detection of neurodegenerative diseases are also a part of the invention.

What is claimed is:  
     
         1 . A method for identifying a compound to treat or prevent the onset of a neurodegenerative disorder, said method comprising the steps of: 
 a) providing a cell comprising a reporter gene operably linked to a cAMP regulatory gene or promoter;    b) contacting said cell with a candidate compound; and    c) measuring expression of said reporter gene, a change in said expression in response to said candidate compound identifying a compound that is useful to treat or prevent the onset of a neurodegenerative disorder.    
     
     
         2 . The method of  claim 1 , wherein said cAMP regulatory gene is an acy-1 gene.  
     
     
         3 . The method of  claim 1 , wherein said cAMP regulatory gene is an eat-4 gene.  
     
     
         4 . The method of  claim 1 , wherein said cAMP regulatory gene is an unc-36 gene.  
     
     
         5 . The method of  claim 1 , wherein said cAMP regulatory gene is a glutamate receptor.  
     
     
         6 . The method of  claim 1 , wherein said change in said expression is a decrease in expression.  
     
     
         7 . The method of  claim 1 , wherein said cell is present in an animal.  
     
     
         8 . The method of  claim 7 , wherein said animal is a nematode.  
     
     
         9 . The method of  claim 8 , wherein said nematode is  C. elegans.    
     
     
         10 . The method of  claim 7 , wherein said animal is a mammal.  
     
     
         11 . The method of  claim 10 , wherein said mammal is a rodent.  
     
     
         12 . The method of  claim 1 , wherein said neurodegenerative disorder is Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, stroke, or epilepsy.  
     
     
         13 . A cell for identifying a compound to treat or prevent the onset of a neurodegenerative disorder, said cell comprising a reporter gene operably linked to a promoter of a cAMP regulatory gene.  
     
     
         14 . The cell of  claim 13 , wherein said cell is present in an animal.  
     
     
         15 . The cell of  claim 14 , wherein said animal is  C. elegans.    
     
     
         16 . The cell of  claim 14 , wherein said animal is a rodent.  
     
     
         17 . The cell of  claim 13 , wherein said neurodegenerative disorder is Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, stroke, or epilepsy.  
     
     
         18 . A method for treating or preventing the onset of a neurodegenerative disorder in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a compound that decreases a neuronal cAMP level.  
     
     
         19 . The method of  claim 18 , wherein said mammal is a human.  
     
     
         20 . The method of  claim 19 , wherein said neurodegenerative disorder is Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, stroke, or epilepsy.  
     
     
         21 . A method for identifying a mammal having or likely to develop a neurodegenerative disorder, said method comprising determining whether said mammal has an increased level of cellular cAMP in a neuron, said increased level indicating that said mammal has or is likely to develop a neurodegenerative disorder.  
     
     
         22 . A method for identifying a mammal having or likely to develop a neurodegenerative disorder, said method comprising determining whether said mammal has a mutation in a cAMP regulatory gene, said mutation being an indication that said mammal has or is likely to develop a neurodegenerative disorder.  
     
     
         23 . The method of  claim 22 , wherein said mutation is in an adenylyl cyclase gene.  
     
     
         24 . The method of  claim 23 , wherein said adenylyl cyclase gene is the acy-1 gene.  
     
     
         25 . The method of  claim 22 , wherein said mutation is in the unc-36 gene.  
     
     
         26 . The method of  claim 22 , wherein said mutation is in the eat-4 gene.  
     
     
         27 . The method of  claim 22 , wherein said mutation is in a gene encoding a Gα s  subunit.  
     
     
         28 . The method of  claim 22 , wherein said mutation results in an increase in a neuronal cAMP level.  
     
     
         29 . The method of  claim 21  or  22 , wherein said mammal is a human.  
     
     
         30 . The method of  claim 29 , wherein said neurodegenerative disorder is Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, stroke, or epilepsy.  
     
     
         31 . A method for identifying a gene involved in neurodegeneration, said method comprising the steps of: 
 a) providing a nematode comprising an expression construct, said expression construct comprising a promoter derived from a cAMP regulatory gene operably linked to a reporter gene;    b) isolating a mutant of said nematode exhibiting an altered level of reporter gene expression; and    c) identifying said gene comprising said mutation, said gene being involved in neurodegeneration.    
     
     
         32 . A method for identifying a gene involved in neurodegeneration, said method comprising the steps of: 
 a) providing a nematode comprising a glutamate receptor (GluR) promoter operably linked to a gene encoding a GTP-ase defective Gα s  subunit;    b) isolating a mutant of said nematode exhibiting a decreased level of paralysis and neurodegeneration; and    c) identifying said gene comprising said mutation, said gene being involved in neurodegeneration.    
     
     
         33 . The method of  claim 31  and  32 , wherein said nematode is  C. elegans.    
     
     
         34 . A method for identifying a gene involved in neurodegeneration, said method comprising the steps of: 
 (a) providing a cell comprising a cAMP regulatory gene promoter operably linked to a reporter gene;    (b) introducing into said cell a candidate gene capable of expressing a candidate protein; and    (c) measuring reporter gene expression in said cell, an increase in said reporter gene expression in the presence of said candidate protein indicating that said candidate gene is involved in neurodegeneration.    
     
     
         35 . The method of  claim 34 , wherein said cell is yeast.  
     
     
         36 . The method of  claim 34 , wherein said cAMP regulatory gene is an acy-1 gene.  
     
     
         37 . The method of  claim 34 , wherein said cAMP regulatory gene is an eat-4 gene.  
     
     
         38 . The method of  claim 34  wherein said cAMP regulatory gene is an unc-36 gene.  
     
     
         39 . The method of  claim 34 , wherein said cAMP regulatory gene is a glutamate receptor-encoding gene.  
     
     
         40 . A mammalian EAT-4 polypeptide.  
     
     
         41 . A purified nucleic acid encoding the polypeptide of  claim 40 .  
     
     
         42 . The nucleic acid of  claim 41 , wherein said mammal is a human.  
     
     
         43 . A vector comprising the nucleic acid of  claim 41  said vector being capable of directing expression of the said polypeptide in a vector-containing cell.  
     
     
         44 . A cell that contains the nucleic acid of claim  41 .