Exploring Protein Quality Control Dysfunction in Dystonia
Abstract
This Investigator-initiated Research Award proposal is made in response to the Fiscal Year 2020 Peer Reviewed Medical Research Program with a focus on the topic area Dystonia. Dystonia is a highly debilitating movement disorder that encompasses both congenital and spontaneous forms, affecting about 250,000 people in the United States alone. Thus, dystonia ranks among the most frequent movement disorders in humans. Patients present with abnormal postures, pain, repetitive involuntary muscle contractions and movements, or a combination of these symptoms, materially compromising their quality of life. Although progress has been made for the treatment of some forms of this disease, there is presently no curative therapy. Available treatments have either significant side effects and/or require invasive procedures that can only be performed by a small number of specialized centers to which not all patients have access. In either case, the therapeutic benefit is often incomplete or transient and comes at the cost of significant side effects or complications, creating the need for additional innovative therapies. A key limitation towards developing novel strategies for dystonia treatment is that the molecular cause of the disease is poorly understood both for congenital and spontaneous forms. Consequently, the molecular machines and cellular processes that malfunction during dystonia are unknown or incompletely understood, causing a major deficiency in our knowledge about cellular targets that can be attacked or corrected for the purpose of treatment. In recent years, the Principal Investigator’s laboratory has focused on illuminating fundamental cellular processes that are compromised in a congenital form of dystonia called DYT1 dystonia. DYT1 dystonia, which is caused by a mutation in the protein TorsinA, is the most frequent and severe form of dystonia. We and other laboratories in the field have defined the molecular defect resulting from the DYT1 mutation, and assigned TorsinA to a critical function in nuclear pore complex (NPC) biogenesis, a process we find to be perturbed in DYT1 dystonia. As NPCs serve as channels that are essential for trafficking of cargo in and out of the cell’s nucleus, defects in nuclear transport likely contribute to the disease pathology on a cellular level. In studying this process and specifically how NPC defects contribute to disease, we made the unexpected discovery that molecular chaperones – molecular machines that govern protein quality control and play important roles in the assembly of lager protein complexes – are highly concentrated at defective NPC assembly sites. This observation immediately suggests that chaperones identified by us are required for NPC biogenesis, and that this fundamental process is perturbed in DYT1 dystonia. We therefore propose to scrutinize this process and probe if chaperones are implicated in NPC assembly. We will also exploit our observation of mis-localized chaperone machinery in a cell-based model system of dystonia; our goal is to develop antibodies against these chaperones as biomarkers that can be readily used in a range of other model systems, including spontaneous or trauma-induced forms of dystonia. A second important line of investigation will focus on cellular protein homeostasis and its perturbation through Torsin deficiency. This presently underexplored angle is motivated by our recent observation that some of the major molecular chaperones are sequestered away from their normal sites of action and become immobilized at defective NPC assembly sites in Torsin-deficient cells. Based on these observations and our unpublished genetic and biochemical results, we hypothesize that the cellular protein homeostasis network is materially compromised in DYT1 dystonia. This concept could extend to spontaneous forms of the disease, and represent an important parameter contributing to the variable penetrance of congenital forms of dystonia. Therefore, we pro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110717
Entities
People
- Christian Schlieker
Organizations
- United States Army
- Yale University