TorsinA mediated regulation of Cdc42 signaling and DYT1 dystonia

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PROJECT SUMMARY/ABSTRACT DYT1 dystonia is a devastating neurological movement disorder characterized by uncontrolled muscle contractions that result in abnormal, involuntary postures. DYT1 dystonia is caused by a deletion (Δgag; ΔE) in the Tor1A gene encoding the luminal ATPases associated with various cellular activities (AAA+) protein torsinA. How the ΔE mutation causes DYT1 dystonia remains unclear because the basic cellular function performed by torsinA is unknown. This proposal seeks to close these critical gaps in knowledge, which will enable the rational design of urgently needed targeted therapies. Our recent work suggests that torsinA is i) required for the transduction of mechanical signals from the cytoskeleton into the nucleoplasm via the nuclear envelope spanning linker of nucleoskeleton and cytoskeleton (LINC) complex; ii) the activation of signaling mediated by the Rho GTPase Cdc42; iii) as well as proper axon outgrowth and growth cone morphology. Importantly, axonal tract disruptions that correlate with clinical severity are observed in the brains of DYT1 dystonia patients and the both the LINC complex and Cdc42 mediate axon elongation and guidance. Thus, we hypothesize that defective torsinA-dependent mechano-chemical signal transduction contributes to DYT1 dystonia pathogenesis. We will test this hypothesis in cultured mammalian cells and the African clawed frog Xenopus laevis using an array of established and novel biochemical, biophysical, fluorescent Rho GTPase biosensors, quantitative imaging and proteomics, as well as synthetic biological approaches. In this proposal, we will define how torsinA and its co-activator, the inner nuclear membrane protein LAP1, regulate the assembly of functional LINC complexes in cultured mammalian cells (Aim 1). We will determine how torsinA and its other co-activator, the outer nuclear membrane protein LULL1, control the activation of Cdc42 in cultured mammalian cells (Aim 2). Finally, we will test the role of torsinA-dependent mechano-chemical signal transduction during axon outgrowth in cultured X. laevis neurons and in the brains of living embryos (Aim 3). The results of these Aims will provide invaluable mechanistic insights into the emerging role of the nuclear envelope as a signaling node in development and disease. Furthermore, they will lay the foundation for the future development of novel therapeutic strategies for the treatment of other forms of dystonia, dystonia plus syndromes in which dystonia can occur in conjunction with another neurological disorder such as Huntington's and Parkinson's diseases, as well as other neurologic and neuropsychiatric diseases caused by mutations in LINC complex proteins including autism, ataxia, bipolar disorder, dementia, and schizophrenia.