Transposable elements, tdp-43, and neurodegenerative disorders

Abstract

A method that includes measuring the expression level of at least one transposon in a biological sample from a subject; and determining whether the measured transposon expression exceeds a predetermined level, and if so, administering to the subject a transposon inhibitor in an amount effective to reduce the expression level of a transposon.

1 - 105 . (canceled) 
     
     
         106 . A method of treatment, comprising
 administering to a subject having a TDP-43 associated neurodegenerative disorder a transposon inhibitor in an amount effective to reduce the expression level of a transposon, wherein the TDP-43 associated neurodegenerative disorder is selected from the group consisting of frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), corticobasal degeneration, chronic traumatic encephalopathy, a disorder associated with repetitive head injury, and a Lewy body (LB) related disorder.   
     
     
         107 . The method of  claim 106 , further comprising testing for the presence of a TDP-43 associated cytoplasmic inclusion in the subject. 
     
     
         108 . The method of  claim 106 , wherein the neurodegenerative disorder is frontotemporal lobal degeneration (FTLD), amyotrophic lateral sclerosis (ALS), or Alzheimer disease (AD). 
     
     
         109 . The method of  claim 106 , wherein the neurodegenerative disorder is corticobasal degeneration. 
     
     
         110 . The method of  claim 106 , wherein the neurodegenerative disorder is chronic traumatic encephalopathy. 
     
     
         111 . The method of  claim 106 , wherein the neurodegenerative disorder is a disorder associated with repetitive head injury. 
     
     
         112 . The method of  claim 106 , wherein the neurodegenerative disorder is a Lewy body (LB) related disorder. 
     
     
         113 . The method of  claim 106 , wherein the Lewy body related disorder is selected from the group consisting of Parkinson disease without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer disease (AD). 
     
     
         114 . The method of  claim 106 , wherein the transposon inhibitor is an inhibitor of a protein encoded by a transposon. 
     
     
         115 . The method of  claim 106 , wherein the protein encoded by the transposon is a transposase; an integrase; a reverse transcriptase; an endonuclease; a protein encoded by gag, pal, or env; an enzyme encoded by ORF1, or an enzyme encoded by ORF2. 
     
     
         116 . The method of  claim 106 , wherein the transposon inhibitor is an anti-retroviral drug; an inhibitor of reverse transcription; an inhibitor of transposase or integrase activity; an inhibitor of endonuclease activity; a stimulator of DNA repair machinery; a zinc-finger that targets a transposon promoter region; a repressor that inhibits a transposon; an innate antiretroviral resistance factor; a small interfering RNAs (siRNA), short hairpin RNA (shRNA), morpholine, or antisense oligonucleotide directed to a TE transcript; an inhibitor that blocks intercellular transmission of transposon genetic material or protein, or an inhibitor of post-translational processing or proteolysis of a transposon-encoded protein. 
     
     
         117 . The method of  claim 106 , wherein the transposon is a retrotransposon. 
     
     
         118 . The method of  claim 117 , wherein the retrotransposon is an LTR-retrotransposon. 
     
     
         119 . The method of  claim 117 , wherein the retrotransposon is a non-LTR retrotransposon. 
     
     
         120 . The method of  claim 119 , wherein the non-LTR retrotransposon is a LINE retrotransposon. 
     
     
         121 . The method of  claim 120 , wherein the LINE retrotransposon is L1. 
     
     
         122 . The method of  claim 119 , wherein the non-LTR retrotransposon is a SINE retrotransposon. 
     
     
         123 . The method of  claim 122 , wherein the SINE retrotransposon is an Alu sequence. 
     
     
         124 . The method of  claim 106 , wherein the transposon is a DNA transposon. 
     
     
         125 . The method of  claim 106 , wherein the transposon is an autonomous element. 
     
     
         126 . The method of  claim 106 , wherein the transposon is a nonautonomous element. 
     
     
         127 . The method of  claim 117 , wherein the retrotransposon includes a gypsy element. 
     
     
         128 . The method of  claim 106 , wherein the subject is a human. 
     
     
         129 . A method of treatment, comprising:
 (a) administering to a subject having a TDP-43 associated neurodegenerative disorder a transposon inhibitor in an amount effective to reduce the expression level of a transposon;   (b) measuring the expression level of at least one transposon in a biological sample from the subject; and   (c) determining whether the measured transposon expression level in the subject exceeds a predetermined level,   wherein the TDP-43 associated neurodegenerative disorder is selected from the group consisting of frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), corticobasal degeneration, chronic traumatic encephalopathy, a disorder associated with repetitive head injury, and a Lewy body (LB) related disorder.   
     
     
         130 . The method of  claim 129 , wherein the transposon is a retrotransposon. 
     
     
         131 . The method of  claim 130 , wherein the retrotransposon comprises a gypsy element. 
     
     
         132 . The method of  claim 129 , wherein the subject is a human. 
     
     
         133 . A method of determining whether a test subject is afflicted with a TDP-43 associated neurodegenerative disorder, the method comprising
 (a) measuring the expression level of at least one transposon in a test sample from the test subject, and   (b) comparing the expression level in the test sample to a control expression level of the at least one transposon in a control subject that is not afflicted with the TDP-43 associated disorder,   wherein a significant difference between the expression level in the test sample and the control expression level is an indication that the test subject is afflicted with a TDP-43 associated neurodegenerative disorder,   
     
     
         134 . The method of  claim 133 , further comprising testing for the presence of a TDP-43 associated cytoplasmic inclusion in the subject. 
     
     
         135 . The method of  claim 133 , wherein the neurodegenerative disorder is frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), or Alzheimer disease (AD). 
     
     
         136 . The method of  claim 133 , wherein the transposon is a retrotransposon. 
     
     
         137 . The method of  claim 136 , wherein the retrotransposon includes a gypsy element.