Dystonia is a family of movement disorders characterized by involuntary muscle contractions leading to abnormal posture and twisting movements, and is the third most common movement disorder after essential tremor and Parkinson's disease. Dystonia can occur with or without other neurological symptoms, and oftentimes occurs with movement disorders such as Parkinson's disease. Recently, mutations in the gene THAP1 have been shown to cause a genetic dystonia (DYT-THAP1), a primary torsion dystonia. The gene THAP1 encodes the protein Thap1 (Thanatos-associated domain-containing apoptosis-associated protein 1) a putative zinc-dependent transcription factor. Our lab studies various movement disorders all of which have dystonia as one of the possible symptoms. I have generated a novel Thap1 knockout mouse that I will use to study DYT-THAP1 as well as the role of Thap1 in the central nervous system. I will be using a variety of molecular biological and biochemical assays to determine the role of Thap1 in the nervous system, and how mutations in Thap1 can lead to dystonia. My overarching hypothesis is that DYT-THAP1 is caused by a loss of function of Thap1, specifically a loss of its transcriptional properties affecting gene expression. I will begin by characterizing a novel mouse model (Aim 1), and determining how Thap1 levels and mutations affect neuronal growth and survival (Aim 2). This study will provide insight into the role of Thap1 in the nervous system, and provide a mouse model for studying DYT-THAP1.
Dystonia is a family of movement disorders, either in conjunction with other neurological diseases such as Parkinson's disease or by itself, characterized by involuntary and abnormal movements. While there are few effective treatments, I am working on characterizing a novel mouse model that removes the gene of interest in the nervous system in order to better understand this disorder for eventual therapeutic intervention and the role of the gene in the nervous system.
