Detection and treatment of schizophrenia

Abstract

The present invention provides a method for diagnosing schizophrenia, and a schizophrenia diagnostic reagent or device for use in the method. The present invention further provides a therapeutic or ameliorating agent for schizophrenia, which is effective for the treatment or amelioration of schizophrenia. The therapeutic or ameliorating agent for schizophrenia contains a carbonyl scavenger or a carbonyl-modified protein formation inhibitor as an active ingredient. The method for diagnosing schizophrenia according to the present invention includes measuring at least one parameter in a subject, the parameter being selected from the group consisting of: (1) a genetic abnormality of glyoxalase I gene; (2) the expression level or activity of glyoxalase I in a biological sample; (3) the amount of a carbonyl compound or a carbonyl-modified protein that is a protein modified with the carbonyl compound; and (4) the amount of pyridoxal in a biological sample.

1 . A method for diagnosing schizophrenia comprising measuring at least one parameter in a subject, the parameter being selected from the group consisting of:
 (1) a genetic abnormality of glyoxalase I gene;   (2) the expression level or activity of glyoxalase I in a biological sample;   (3) the amount of a carbonyl compound or a carbonyl-modified protein that is a protein modified with the carbonyl compound in a biological sample; and   (4) the amount of pyridoxal in a biological sample.   
     
     
         2 . The method for diagnosing schizophrenia according to  claim 1 , further comprising measuring (5) the amount of homocysteine in a biological sample when (4) the amount of pyridoxal in the biological sample is measured. 
     
     
         3 . The method for diagnosing schizophrenia according to  claim 1 , wherein (1) the genetic abnormality of glyoxalase I gene is a frame shift mutation caused by adenine insertion between adenine at position 79 and cytosine at position 80 in a base sequence (SEQ ID NO: 2) of a coding region of glyoxalase I gene shown in SEQ ID NO: 1. 
     
     
         4 . The method for diagnosing schizophrenia according to  claim 1 , wherein (1) the genetic abnormality of glyoxalase I gene is a base substitution mutation that changes the amino acid residue at position 111 from Glu to Ala in an amino acid sequence of glyoxalase I shown in SEQ ID NO: 3. 
     
     
         5 . The method for diagnosing schizophrenia according to  claim 1 , wherein the subject has a genetic abnormality of glyoxalase I gene that lowers glyoxalase I activity, the method comprising measuring at least one parameter selected from the group consisting of the above parameters (2) to (4) in the subject. 
     
     
         6 . The method for diagnosing schizophrenia according to  claim 5 , wherein the genetic abnormality of glyoxalase I gene is a frameshift mutation caused by either adenine insertion between adenine at position 79 and cytosine at position 80 in a base sequence (SEQ ID NO: 2) of a coding region of glyoxalase I gene shown in SEQ ID NO: 1, or a base substitution mutation that changes the amino acid residue at position 111 from Glu to Ala in an amino acid sequence of glyoxalase I shown in SEQ ID NO: 3. 
     
     
         7 . The method for diagnosing schizophrenia according to  claim 1 , wherein (3) the amount of the carbonyl-modified protein is measured by an immunoassay using an anti-carbonyl-modified protein antibody, high performance liquid chromatography, gas chromatography/mass spectrometry, or a method using an AGE-Reader. 
     
     
         8 . The method for diagnosing schizophrenia according to  claim 1 , wherein the carbonyl-modified protein is pentosidine. 
     
     
         9 . The method for diagnosing schizophrenia according to  claim 1  comprising the steps of:
 (A) measuring at least one parameter in a subject, the parameter being selected from the group consisting of: 
 
       (2) the expression level or activity of glyoxalase I in a biological sample; 
       (3) the amount of a carbonyl-modified protein that is a protein modified with the carbonyl compound in a biological sample; and 
       (4) the amount of pyridoxal in a biological sample; and
 (B) comparing a parameter value obtained in step (A) with a healthy person's value of the same parameter (a control value). 
 
     
     
         10 . The method for diagnosing schizophrenia according to  claim 9 , wherein the subject is diagnosed as having schizophrenia or as likely developing schizophrenia in the future when the parameter value of the subject meets the following conditions:
 (2) the expression level or activity of glyoxalase I in the biological sample of the subject is lower than that of a healthy person;   (3) the amount of the carbonyl-modified protein in the subject is larger than that of a healthy person; or   (4) the amount of pyridoxal in the subject is smaller than that of a healthy person.   
     
     
         11 . A primer comprising a labeled or unlabeled 15- to 35-base oligonucleotide which hybridizes with a continuous oligo- or polynucleotide of 16 or more bases comprising adenine at position 79 and cytosine at position 80, or a continuous oligo- or polynucleotide of 16 or more bases comprising a base at position 332, in a base sequence (SEQ ID NO: 2) of a coding region of glyoxalase I gene shown in SEQ ID NO: 1 (when the oligo- or polynucleotide is RNA, the base “t” in the base sequence is replaced with “u”), and which is used for specifically amplifying the continuous oligo- or polynucleotide, and identifying adenine insertion between adenine at position 79 and cytosine at position 80, or mutation at position 332 from adenine to cytosine, in the base sequence (SEQ ID NO: 2) of a coding region of glyoxalase I gene shown in SEQ ID NO: 1 to diagnose schizophrenia in a subject. 
     
     
         12 . A probe comprising a labeled or unlabeled 16- to 500-base oligonucleotide which hybridizes with a continuous oligo- or polynucleotide of 16 or more bases comprising adenine at position 79 and cytosine at position 80, or a continuous oligo- or polynucleotide of 16 or more bases comprising a base at position 332, in a base sequence (SEQ ID NO: 2) of a coding region of glyoxalase I gene shown in SEQ ID NO: 1 (when the oligo- or polynucleotide is RNA, the base “t” in the base sequence is replaced with “u”), and which is used for specifically detecting the continuous oligo- or polynucleotide and identifying adenine insertion between adenine at position 79 and cytosine at position 80, or mutation at position 332 from adenine to cytosine, in the base sequence (SEQ ID NO: 2) of a coding region of glyoxalase I gene shown in SEQ ID NO: 1 to diagnose schizophrenia in a subject. 
     
     
         13 . A reagent comprising the primer of  claim 11  and/or the probe of  claim 12 . 
     
     
         14 . A kit comprising the reagent of  claim 13 . 
     
     
         15 . The method for diagnosing schizophrenia according to  claim 3 , comprising measuring (1) a genetic abnormality of glyoxalase I gene by using a primer comprising a labeled or unlabeled 15- to 35-base oligonucleotide which hybridizes with a continuous oligo- or polynucleotide of 16 or more bases comprising adenine at position 79 and cytosine at position 80, or a continuous oligo- or polynucleotide of 16 or more bases comprising a base at position 332, in a base sequence (SEQ ID NO: 2) of a coding region of glyoxalase I gene shown in SEQ ID NO: 1 (when the oligo- or polynucleotide is RNA, the base “t” in the base sequence is replaced with “u”), and which is used for specifically amplifying the continuous oligo- or polynucleotide, and identifying adenine insertion between adenine at position 79 and cytosine at position 80, or mutation at position 332 from adenine to cytosine, in the base sequence (SEQ ID NO: 2) of a coding region of glyoxalase I gene shown in SEQ ID NO: 1 to diagnose schizophrenia in a subject. 
     
     
         16 . The method for diagnosing schizophrenia according to  claim 3 , comprising measuring (1) a genetic abnormality of glyoxalase I gene by using a probe comprising a labeled or unlabeled 16- to 500-base oligonucleotide which hybridizes with a continuous oligo- or polynucleotide of 16 or more bases comprising adenine at position 79 and cytosine at position 80, or a continuous oligo- or polynucleotide of 16 or more bases comprising a base at position 332, in a base sequence (SEQ ID NO: 2) of a coding region of glyoxalase I gene shown in SEQ ID NO: 1 (when the oligo- or polynucleotide is RNA, the base “t” in the base sequence is replaced with “u”), and which is used for specifically detecting the continuous oligo- or polynucleotide and identifying adenine insertion between adenine at position 79 and cytosine at position 80, or mutation at position 332 from adenine to cytosine, in the base sequence (SEQ ID NO: 2) of a coding region of glyoxalase I gene shown in SEQ ID NO: 1 to diagnose schizophrenia in a subject