Molecular diagnostic method and treatment in dementia with Lewy bodies

Abstract

The invention describes methods of molecular diagnosis of a concrete form of α-synucleinopathy, the dementia with Lewy bodies (DLB), associated to the levels of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) or the alteration of its ubiquityl-ligase activity. It also refers to the use of compounds that permit the modification of the UCH-L1 levels or of the enzymatic activity of UCH-L1. This invention has application in the diagnosis and treatment of patients suffering from DLB.

1 . A method of diagnosing dementia with Lewy bodies (DLB) in a patient suspected of having the onset of said DLB, said method comprising:
 analyzing a sample obtained from the patient to determine the level of expression of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene, wherein a reduced a level of expression of UCH-L1 gene compared to a control is diagnostic of DLB.   
     
     
         2 . The method according to  claim 1 , wherein said analyzing comprises determining the level of RNA or protein corresponding to UCH-L1. 
     
     
         3 . The method according to  claim 1 , wherein said analyzing comprises determining the level of protein corresponding to UCH-L1. 
     
     
         4 . The method according to  claim 1 , wherein said sample is isolated from a biological fluid selected from the group consisting of cerebrospinal fluid, serum, and urine. 
     
     
         5 . The method according to  claim 1 , wherein said sample is isolated from cells of neural tissue. 
     
     
         6 . The method according to  claim 1 , wherein said sample is isolated from peripheral neuroendocrine cells. 
     
     
         7 . The method according to  claim 1 , wherein determining the level of expression of UCH-L1 gene is performed by PCR amplification, SDA amplification, or any other method of amplification of cDNA that permits a quantitative estimation of the UCH-L1 transcript levels. 
     
     
         8 . The method according to  claim 1 , wherein determining the level of expression of UCH-L1 gene is performed by a DNA biochip having oligonucleotides deposited thereon. 
     
     
         9 . The method according to  claim 1 , wherein determining the level of expression of UCH-L1 gene is performed by analyzing via Western blot the amount of protein present, by “protein-chip” using specific antibodies against UCH-L1, by protein profiles obtained by mass spectrometry, or by any other mechanism that permits a quantitative estimation of the UCH-L1 protein levels. 
     
     
         10 . A method of improving a diagnosis of dementia with Lewy bodies (DLB) in a subject, the method comprising:
 obtaining a sample from the subject; and   analyzing the level of expression of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene in the sample, wherein reduced levels of expression of UCH-L1 gene is diagnostic of DLB, thereby improving the diagnosis of DLB in the subject.   
     
     
         11 . The method according to  claim 10 , wherein said analyzing comprises determining the level of RNA or protein corresponding to UCH-L1. 
     
     
         12 . The method according to  claim 10 , wherein said analyzing comprises determining the level of protein corresponding to UCH-L1. 
     
     
         13 . The method according to  claim 10 , wherein said sample is isolated from a biological fluid selected from the group consisting of cerebrospinal fluid, serum, and urine. 
     
     
         14 . The method according to  claim 10 , wherein said sample is isolated from cells of neural tissue. 
     
     
         15 . The method according to  claim 10 , wherein said sample is isolated from peripheral neuroendocrine cells. 
     
     
         16 . The method according to  claim 10 , wherein determining the level of expression of UCH-L1 gene is performed by PCR amplification, SDA amplification, or any other method of amplification of cDNA that permits a quantitative estimation of the UCH-L1 transcript levels. 
     
     
         17 . A method of screening for a compound for treating dementia with Lewy bodies (DLB), said method comprising:
 providing a compound and   analyzing the compound's ability to increase ubiquitin carboxy-terminal hydrolase UCH-L1 expression.   
     
     
         18 . The method of  claim 17 , comprising analyzing the compound's ability to increase UCH-L1 gene transcription. 
     
     
         19 . The method of  claim 17 , comprising analyzing the compound's ability to increase UCH-L1 protein levels. 
     
     
         20 . The method of  claim 17  wherein said analyzing comprises contacting said compound with a cell or cells.