Major Advancements in Understanding Dystonia Biochemistry

Researchers Target TorsinA for Answers

11/7/16

In the next issue of the Dystonia Dialogue, look for an information-packed update on the progress researchers are making on de-mystifying TorsinA, a protein known to cause dystonia when it becomes abnormal due to genetic mutation. TorsinA is infamous for its role in causing DYT1 early onset dystonia but is also suspected to play a role in additional types of dystonia. The past several months have produced an explosion of groundbreaking new published data on TorsinA—including some surprises.

TorsinA to the Rescue

A team of researchers led by DMRF Stanley Fahn Award recipient William Dauer, MD at University of Michigan and DMRF research fellowship recipient Lauren Tanabe, PhD, now of Wayne State University, has made remarkable strides in clarifying the biochemical origins of DYT1 dystonia. In a series of studies in animal and cell models, they have found that a loss of TorsinA function leads to abnormal formations in brain cells and brain cell death. These damaging effects occur only during the window of time when symptoms develop. The investigators’ latest experiments have shown that the impaired brain cells can be rescued by healthy TorsinA and a related protein, TorsinB. These proteins are critical to the survival of brain cells and can actually save brain cells from the damaging effects of abnormal TorsinA.

Surprise! TorsinA Regulates Lipid Metabolism 

A former trainee of Dr. Dauer and member of the DMRF’s Medical & Scientific Advisory Council is making additional landmark discoveries about the role of TorsinA in cells. The function of this protein is yet another mystery that may soon be solved. Rose Goodchild, PhD at University of Leuven in Belgium has used fruit flies to show that TorsinA regulates lipid metabolism. Lipids are fat molecules and have important roles in the structure and function of living cells, including brain cells. This unexpected discovery provides new insight into the physiological roles of TorsinA and opens up new opportunities for therapeutic strategies to treat or prevent dystonia symptoms. 

Role in Calcium Physiology

Longtime dystonia investigator and DMRF Stanley Fahn Award recipient Pedro Gonzalez-Alegre, MD, PhD, continues to publish discoveries on TorsinA. In his latest paper, he reveals that TorsinA has a role in calcium physiology—an observation not made before. Healthy TorsinA helps protect cells from the effects of stress, but mutant TorsinA causes an inadequate stress response that interferes with protein metabolism and affects calcium turnover. Additional dystonia proteins play a role in cell stress responses and in regulating calcium. Dr. Gonzalez-Alegre’s work provides a point of intersection for research investigations exploring the molecular origins of various forms of dystonia, inspiring new questions to explore.

TorsinA Takes Shape

At Massachusetts Institute of Technology, researchers led by DMRF grant recipient and Medical & Scientific Advisory Council member Thomas Schwartz, PhD have used sophisticated crystallography technology to reveal the shape and structure of the TorsinA protein. Dr. Schwartz has successfully described the atomic structure of both healthy and abnormal TorsinA, providing a novel perspective from which to ask new questions and design new experiments. 

Look for a more detailed discussion of these important discoveries in the next Dystonia Dialogue, to be published this month. Not yet a subscriber? Start or renew your membership here.

The DMRF is proud to partner with the charitable foundation Cure Dystonia Now to fund projects focused on TorsinA in 2016. For information on these and all DMRF-funded research projects, visit dystonia-foundation.org/research.

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