Dystonia can be caused by genetic defects and abnormally functioning proteins and cellular pathways

Genetic discoveries have been guiding dystonia research for a number of years now. Typically, once new genes have been discovered a quest for understanding the role of their corresponding proteins begins. Since multiple dystonia genes have been linked to various forms of dystonia, major efforts are underway to find out if there is an overlap between different dystonia mechanisms with the hope that there is some commonality between these mechanisms and that this may help in designing more effective and universal therapies. Several studies that tackle these issues are now funded by DMRF.

A group at Yale University, led by Patrick Lusk and Christian Schlieker, continues their work on the role of torsinA in the assembly of other proteins that form the so-called nuclear pore complex, simply a ‘gate’ in the nuclear membrane of the cell, which ensures that only specific molecules can traverse the membrane. This is critical for genetic and metabolic regulation of the entire cell. They uncovered a novel link between nuclear pores and torsinA, especially the pathogenic form that causes DYT1 dystonia. Further, they hypothesize that a disruption of nuclear pore assembly by mutant torsinA leads to the loss of the highly regulated and essential transport of specific cargo molecules in and out of the cell nucleus. Results from their study substantially advance our understanding of torsinA (dys)function, and facilitate the development of more effective treatment strategies.

Another group in Leuven (Belgium), led by Patrick Verstreken and Rose Goodchild, recently identified that mouse torsinA, human torsinA, and fly torsin regulate cellular lipid metabolism. Lipids are small molecules that are the building blocks of cell membranes. There are a wide variety of different types of lipids, and their data indicate that torsin activity is critical for the normal balance of lipid production. Their hypothesis is that abnormal lipid biology is the origin of DYT1 dystonia. The group investigates how abnormal torsin lipid biology affects neurons, and relate this to the endoplasmic reticulum defects previously described in torsin model systems. It is also vital to build a cloud of mechanistic information around torsin regulated lipid biology in order for the field and industry to be confident that lipid metabolism is indeed a key target for DYT1 dystonia. Their methods and approaches in this area have been recently patented.

A more integrative approach has been undertaken by Nicole Calakos at Duke University. Her project advances our understanding of dystonia mechanisms and explores specific cellular pathways to target in order to treat the disease. Observations in multiple forms of dystonia have implicated a specific cellular pathway in the brain as a central source of dysfunction. This pathway is involved in responding to cellular stressors and mediating plasticity responses in the brain. This research identifies the brain regions, cell types, and developmental periods in which the pathway’s activation is disrupted in dystonia mouse models and to test whether a genetic manipulation that would boost the pathway’s activity will reduce negative effects of the DYT1 mutation. This knowledge advances our understanding of the cellular mechanism of dystonia and provides key proof-of-principle experiments to determine whether targeting the pathway is beneficial.

A very direct approach is taken by several young postdoctoral investigators who recently received DMRF research fellowships.

Lilian Cruz at Massachusetts General Hospital/Harvard uses the CRISPR/Cas9 system to target specific DYT1 mutation in neurons derived from patient cells. CRISPR/Cas9 is a unique technology that has made headlines as a versatile tool to modify genes by editing DNA. Dr. Cruz is applying this technology to repair isolated neurons that are abnormal due to a dystonia-causing mutation in the DYT1 gene. She also studies how the mutated torsinA protein encoded by the gene interferes with the functions of neurons to reveal mechanisms that can be targeted by new strategies to treat the disorder. She is mentored by Xandra Breakefield, PhD and Cris Bragg, PhD.

Maria Daniela Cirnaru, a postdoctoral fellow in Michelle Ehrlich, MD lab at Mount Sinai Beth Israel studies a different genetic form of dystonia. X-linked dystonia-parkinsonism (XDP) is a rare inherited and degenerative dystonia that affects men from Panay Island in the Philippines. Unlike other dystonias, XDP is characterized by extensive neuron loss in a brain region involved in movement control. Dr. Cirnaru hypothesizes that two causative genes, TAF1 and N-TAF1, control genes and factors that influence the health of these neurons. The intention is to understand the role of TAF1 in the pathogenesis of XDP and accelerate the development of novel therapeutic strategies for this devastating disease and as well as other dystonias where the same brain region is affected.

Another postdoctoral fellow, Anthony Rampello, recently joined Christian Schlieker, PhD at Yale University. He also uses CRISPR technology.  While popular news reports tend to focus on the potential use of CRISPR for genome editing in humans, the primary application has been in basic research using cell and animal models. Thus, Dr. Rampello is using CRISPR to establish a TorsinA interaction map by systemically tracking down genes and proteins that have a functional relationship to TorsinA. Mapping the network of cellular processes in which TorsinA is involved is remains critical to understanding how TorsinA causes dystonia when made dysfunctional by mutations in the DYT1 gene.

Finally, Gabriela Huelgas-Morales, conducting her postdoctoral work with David Greenstein, PhD at the University of Minnesota is using a worm to identify proteins interacting with TorsinA. Since the genetic mutation in DYT1 gene interferes with the ability of TorsinA to function correctly, it is imperative to understand how TorsinA operates normally and what cellular functions go wrong when the protein is dysfunctional. Dr. Morales is using a worm model to identify TorsinA substrates, i.e. proteins that TorsinA acts upon. This is critical to understanding the basic cellular functions of TorsinA and origins of DYT1 childhood dystonia.

It is our sincere hope that all four young fellows will commit themselves to dystonia research and will soon become leaders in their respective fields.