Therapeutic and Diagnostic Method for Ataxia-Telangiectasia

Abstract

ATM kinase is shown to regulate proteasome-mediated protein turnover through suppression of the expression of the ubiquitin-like protein ISG15 (Interferon Stimulated Gene 15). Silencing of the ISG15 pathway restored both the ubiquitin and autophagy pathways, and the UV-mediated degradation of their substrates in A-T cells. The ATM kinase negatively regulates the ISG15 pathway, and the constitutively elevated ISG15 pathway induces proteinopathy in A-T cells, and in A-T patients. These findings indicate that proteasome-mediated protein degradation is impaired in A-T cells due to elevated expression of the ISG15 conjugation pathway, which contributes to progressive neurodegeneration in A-T patients. The ISG15 pathway is a new target for both detection and treatment of A-T. Inhibitors if ISG15 expression can be used to inhibit or attenuate neurodegeneration in A-T patients. In addition, an inhibitor of the early phase of autophagy, 3-MA, was shown to be effective in decreasing the impaired proteasome-mediated protein degradation in A-T cells, and thus would be effective in decreasing the neurodegeneration in A-T patients.

What is claimed: 
     
         1 . An in vitro method to diagnose a patient with Ataxia telangiectasia prone to neurodegeneration, said method comprising the following steps:
 (i) collecting a sample from the patient;   (ii) detecting the level of the protein ISG15 in said sample; and   (iii) comparing the sample ISG15 level to levels of ISG15 in a control sample;   wherein a significantly increased ISG15 level in the patient as compared with the control indicates that the patient is prone to neurodegeneration.   
     
     
         2 . The method of  claim 1 , wherein the sample is selected from the tissue group consisting of cerebrospinal fluid, skin fibroblast cells, peripheral blood cells, plasma, and blood serum. 
     
     
         3 . The method of  claim 1 , wherein the level of the ISG15 is selected from the group consisting of the level of free ISG15, the level of conjugated ISG15, and the level of both free and conjugated ISG15. 
     
     
         4 . The method of  claim 1 , additionally comprising testing the sample for the presence of alpha-fetoprotein. 
     
     
         5 . The method of  claim 1 , additionally comprising testing the sample for the increased levels of autophagy markers selected from the group consisting of LC3-I, LC3-II, mitochondrial superoxide, and mitochondrial mass. 
     
     
         6 . A method to treat or decrease neurodegeneration in a patient with Ataxia telangiectasia, said method comprising administering to the patient an effective amount of an agent that inhibits early stage autophagy. 
     
     
         7 . Them method of  claim 6 , wherein the agent is 3-methyladenine. 
     
     
         8 . A method to diagnose a patient with Ataxia telangiectasia prone to neurodegeneration, said method comprising the following steps:
 (i) collecting a sample from the patient;   (ii) detecting the level of an autophagy marker selected from the group consisting of LC3-I, LC3-II, mitochondrial superoxide and mitochondrial mass in said sample; and   (iii) comparing the sample marker level to levels of the marker in a control sample;   wherein a significantly increased marker level in the patient as compared with the control indicates that the patient is prone to neurodegeneration.   
     
     
         9 . The method of  claim 8 , wherein the sample is selected from the tissue group consisting of cerebrospinal fluid, skin fibroblast cells, peripheral blood cells, plasma, and blood serum. 
     
     
         10 . The method of  claim 8 , additionally comprising testing the sample for the presence of alpha-fetoprotein. 
     
     
         11 . The method of  claim 8 , additionally comprising testing the sample for increased level of ISG15.