NOVEL BIOMARKERS IN HUNTINGTON'S DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disease that causes involuntary movements, behavioral and psychiatric symptoms, cognitive dysfunction and which inexorably leads to death (1). It is caused by the expansion of a triplet repeat on chromosome 4 at the locus of a gene that codes for the 'huntingtin' protein. More recent work has implicated transcriptional deregulation in the pathogenesis of HD. Previous analyses of gene expression in mouse models of HD indicated that mutant huntingtin causes down regulation of several groups of genes in striatum, as well as in skeletal muscle (2,3), suggesting that mutant huntingtin may interfere with transcriptional mechanisms common to many genes. We have found that the known regulatory sequences of these genes contain binding sites for the ubiquitous transcription factor Sp1, suggesting that mutant huntingtin may interfere with gene transcription in many tissues containing Sp1 factor (3,4). Therefore, we hypothesize that mutant huntingtin may deregulate gene expression in blood cells derived from HD subjects. The proposed research study aims to develop a simple diagnostic test for HD onset and progression that is based on the differential gene expression pattern seen in human blood samples. As a result of both central and peripheral biological processes being disrupted in HD, human cells exhibit a gene expression pattern that may be diagnostic for the disease and will be specific for HD. Hence, we are proposing to develop a novel surrogate marker that is both sensitive to predict disease onset in individuals known to carry the genetic mutation on the basis of presymptomatic genetic testing (i.e. individuals who do not yet manifest motor signs) and to monitor disease progression in symptomatic individuals as well as specific to HD. In addition, we will attempt to determine if the involvement of mitochondrial CREB in human mitochondrial gene expression is similar to that observed in mice models of HD. The demonstration that polyglutamine-mediated gene and protein level changes can be detected in tissue outside the CNS raises the possibility that biomarkers of disease progression will be detectable in skin, muscle, blood or other peripherally accessible tissue. Because current clinical trial endpoints for HD remain unsatisfactory, it is hoped that biomarkers can serve as surrogates in clinical trials, much like reduction of cholesterol levels are used to assess the efficacy of drugs that ultimately reduce cardiac arrest from coronary artery disease.