DOD Announces $1.7M in New Dystonia Studies
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The Department of Defense (DOD) has announced three new dystonia research awards made through the Peer Review Medical Research Program. Thanks to the work of the Dystonia Advocacy Network (DAN), Congress first included dystonia on the exclusive list of conditions eligible for study through the Peer-Reviewed Medical Research Program in the FY 2010 Defense Appropriations Bill. Grassroots advocates have successfully kept dystonia in the program every year since, resulting in millions of dollars in additional funding awarded to dystonia investigators.
Military service members are at increased risk of dystonia, in part due to the frequency of traumatic brain injury (TBI) sustained during training and combat operations. TBI occurs when a bump, blow, or jolt to the head or a penetrating head injury disrupts the normal function of the brain.
The latest dystonia investigators to be awarded grants from the Peer-Reviewed Medical Research Program are past DMRF grant recipient Rekha Patel, PhD from University of South Carolina; DMRF Medical & Scientific Advisory Council Member Thomas U. Schwartz, PhD from Massachusetts Institute of Technology; and Fumiaki Yokoi, PhD from the University of Florida. Below is a lay summary of each project from the investigators:
Thomas Schwartz, PhD
Investigator Initiated Award
Massachusetts Institute of Technology
"Investigating the Oligomerization of TorsinA as a Means to Develop DYT1 Dystonia Therapeutics”
Dystonia is a movement disorder characterized by involuntary muscle contractions causing abnormal, often repetitive, movements and/or postures. It is estimated that at least 250,000 people in the United States suffer from this disease. Dystonia can be caused by different factors, including genetics, but also by traumatic brain injury, certain medications, and exposure to certain toxins. The most common form of generalized dystonia, which affects the entire body, is primarily the result of a seemingly minor genetic modification within the protein TorsinA. We know TorsinA is a tiny motor protein inside every cell of the human body, but we do not yet know what this motor does and how it functions. So far, researchers assumed TorsinA behaved similarly to other motor proteins that have been studied previously, but it turns out that these similarities are less pronounced than initially anticipated.
Our proposal builds on the past five years of research in my lab, which significantly advanced knowledge about TorsinA. We were able to establish that TorsinA does not self-activate, as was expected. Instead, TorsinA uses one of two additional proteins, called LAP1 or LULL1, to engage its motor. LAP1 and LULL1 are activators, an important element toward deciphering the biological role of TorsinA, Protein function is dictated by its structure. Therefore, biologists seek to determine the three-dimensional structure of proteins in order to understand them. Traditionally, this is done using X-ray crystallography, a method with which proteins can be observed at atomic detail. This way, we were able to determine the three-dimensional structures of normal TorsinA and the modified (dystonia-causing) protein. This allowed us to reveal the subtle differences between the two proteins in exquisite detail. We were able to show that, due to a subtle change in the structure, the diseased protein cannot be activated anymore. And, perhaps more importantly, it also gave us a first clue as to how the diseased protein may be ‘repaired’ by developing an appropriate drug. Recently, we made another unexpected observation, which is that TorsinA can oligomerize to form long, filamenteous structures. These structures are not formed with the dystonia mutant, indicating yet another, possibly unique, function for TorsinA. In this project, we aim at characterizing these filamentous structures in atomic detail. We hypothesize that they hold essential information about Torsin function. Due to the specific nature of these assemblies, X-ray crystallography alone is not a suitable tool for the analysis. We will instead exploit the dramatic advances in cryo-electron microscopy (cryo-EM) to study these assemblies. Cryo-EM is about to revolutionize structural biology, and in recognition of this, three pioneers in the field were deservedly awarded this years’ Chemistry Nobel Prize. We will use this technology to characterize the TorsinA filaments at medium resolution, which will guide us to achieve high resolution in a tailor-fit hybrid-approach that will exploit again X-ray crystallography and protein engineering. Now we know that TorsinA can polymerize to generate filaments, or, alternatively, bind its activators LAP1/LULL1. Both processes are blocked by the disease mutation, generating a distinct possibility for interference by drugs. The disease mutation is a subtle surface change on the protein that can potentially be rectified by an appropriate small molecule, thus possibly paving the way toward a therapeutic drug. We will screen for such drugs setting up screening assays exploiting the two functional states of TorsinA that we have structurally characterized. We expect that this research will substantively advance our knowledge about TorsinA function, and consequently bring us closer to a possible cure for dystonia.
Click here for a video of Dr. Schwartz talking about his work to solve the structure of TorsinA.
Rekha Patel, PhD
University of South Carolina
“Dysregulation of the PACT-mediated crosstalk between protein kinases PKR and PERK contributes to dystonia 16 (DYT16)”
One of the reasons for a shortage of effective drug therapies for dystonia has been a poor understanding of the molecular pathways affected in patients. Our proposed project is aimed at understanding the disease-causing mechanism involved in dystonia 16 (DYT16). DYT16 is caused by mutations in the PACT gene (also known as PRKRA). DYT16 patients experience childhood onset of the disease, mostly in limbs and then progressing with age to other parts of the body. The first PACT mutation leading to DYT16 was described in 2008, and the list of mutations in PACT leading to DYT16 has now grown to seven different mutations worldwide.
PACT is involved in eIF2 alpha signaling pathway via activation of PKR protein kinase which regulates survival or death decisions in response to endoplasmic reticulum stress. Endoplasmic reticulum is a membranous structure within the cells where proteins are synthesized. Any problems in endoplasmic reticulum affect the overall functioning of the cell and are thus sensed as “endoplasmic reticulum stress.” A myriad of environmental signals lead to endoplasmic reticulum stress in brain and other organs during the course of normal life. PERK is the main protein that is activated in response to endoplasmic reticulum stress and turns on the eIF2 alpha signaling pathway. It is currently unknown how mutations in PACT that cause DYT16 affect PERK activity leading to downstream signaling to PKR and eIF2 alpha in this pathway. We will investigate the effect of DYT16 mutations on the biochemical activity PERK, and the regulatory crosstalk between PERK and PKR pathways. Our proposal centers on examining if the PERK-eIF2 alpha signaling pathway is functioning optimally in the presence of DYT16 mutant forms of PACT protein. This research is innovative because the effect of PACT mutations on PERK has never been previously examined. We propose to explore the presence of a novel branch of the eIF2 alpha signaling pathway and to test the effect of PACT mutations on resolution of endoplasmic reticulum stress by restoring cellular homeostasis. The results are expected to discover a previously unknown branch of this signaling pathway and add significant new knowledge to both basic research as well as to drug development.
Successful completion of our research will, for the first time, present dystonia researchers with a unifying mechanism that is applicable to several inherited forms of dystonia as well as injury-induced late onset dystonia. In addition, these studies will provide very helpful information for development of novel drugs that may be used to alleviate movement disorder in multiple forms of dystonia. The proposed research will thus add a completely new paradigm for basic understanding of how cells respond to endoplasmic reticulum stress signals and help translational research by identifying novel drug targets.
Fumiaki Yokoi, PhD
University of Florida
“Chemogenetic Modulation of Striatal Cholinergic Interneurons in DYT1 Dystonia”
Dystonia is a movement disorder characterized by twisting, repetitive movements, or abnormal postures. Dystonia has multiple causes: brain injury, stroke, genetics, other diseases (such as Parkinson’s or Huntington’s disease), and drug side effects. Military members have an increased risk of traumatic brain injury and developing dystonia during both the combat operations and training period. Moreover, focal task-specific dystonia hand dystonia also occurs in military members. It is often called by different names based on the causal motor tasks, for example, writer’s cramp, typist’s cramp, computer operator’s cramp, and musician’s dystonia. In the military, it also occurs in rowers, rifle shooters, and pistol shooters. It also occurs in dart throwers, long-distance runners, table tennis players, and golfers. Focal task-specific dystonia hand dystonia is triggered by repeated specific motor tasks. Embouchure dystonia is one of the focal task-specific facial dystonias, which is a lip, tongue, jaw, and/or facial muscle movement disorder caused by extensive training of musicians, such as military band woodwind and brass players. Although the brain injury model may seem more relevant to military members who have dystonic symptoms due to brain injury, it is difficult to reproduce the same symptoms in an experimental model. The advantage of the genetic dystonia model is the stability and reproducibility of the motor symptoms, which makes it very useful to analyze the detailed disease mechanism and to develop novel therapeutics. Although anti-cholinergic drug targeting in the cholinergic system has been widely used to treat dystonia patients, it is not well understood how activation or inhibition of cholinergic neurons affects the posture and motor performance. The broad, long-term goals are understanding the cholinergic neuron’s activity in dystonia and developing novel therapeutics. This project employs chemogenetic technology to clarify the direct relationship between the cholinergic neuronal activity and motor symptoms by modulating the neuronal activity. Finding the optimal drug concentration to cure the motor deficits in mutant mice is a goal of this project. Stimulating and inhibiting modulations in the mutant mice will provide a critical insight toward the direction of developing novel therapeutics directly targeting the cholinergic neuronal activity. If modulation of the cholinergic neuronal activity has a cure effect in the dystonia mouse model, it will suggest that developing a drug directly targeting the cholinergic neuronal activity can be a novel approach for dystonia. The findings produced by this study will be useful to treat not only DYT1 dystonia patients, but also additional dystonia patients working in the military and beyond.
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