UC Davis researchers identify mitochondrial TSPO as a promising drug target to protect and repair myelin in multiple sclerosis
Scientists at the University of California, Davis have discovered that targeting a mitochondrial protein called the translocator protein (TSPO) could lead to safer, more effective therapies for multiple sclerosis (MS) and other diseases that involve loss of white matter. The study, published in EMBO Molecular Medicine, used mouse models of MS to show that drugs engaging mitochondrial TSPO can reduce disease severity and encourage recovery of myelin, the fatty insulating sheath that enables rapid nerve signal transmission in the brain and spinal cord.
Background: TSPO and diseases of myelin loss
Multiple sclerosis is an autoimmune disease in which immune cells attack myelin, the insulating layer around nerve fibers. Loss of myelin disrupts electrical signaling in the central nervous system and causes motor, sensory and cognitive impairments. TSPO is a protein located on the outer membrane of mitochondria, the organelles that supply energy to cells. While TSPO has been studied in other contexts, its direct role in MS and myelin repair had not been established prior to this work.
Key findings from the UC Davis study
Using established mouse models of MS, the research team tested etifoxine, a clinically available anxiolytic in Europe known to interact with mitochondrial TSPO. When etifoxine was given before mice showed clinical signs, the treated animals developed less severe disease than untreated controls. Importantly, administration of etifoxine at peak disease also led to measurable improvement in symptoms. Taken together, these results indicate that engagement of mitochondrial TSPO can both reduce the severity of autoimmune myelin injury and support recovery.
Lead investigator Wenbin Deng, associate professor of biochemistry and molecular medicine at UC Davis, described etifoxine’s action as a “novel protective effect against the loss of the sheath that insulates nerve fibers.” The study suggests that mitochondrial TSPO represents a viable therapeutic target for drug development aimed at protecting and repairing myelin in MS.
Therapeutic implications
Current FDA-approved MS therapies primarily focus on modulating the immune system to reduce inflammation and prevent new attacks, but they generally do not repair existing myelin damage. A strategy that targets mitochondrial TSPO could complement immune-based approaches by directly promoting myelin preservation and repair, potentially restoring more normal signal transmission in the central nervous system and improving motor, sensory and cognitive function.
The UC Davis team emphasizes that etifoxine itself provides proof of principle: drugs designed to bind mitochondrial TSPO more selectively and safely may be able to enhance remyelination and functional recovery in patients. To advance this line of research, the investigators plan to pursue funding to screen and test a range of compounds that interact with TSPO and related molecular targets in experimental models of MS and other demyelinating disorders such as cerebral palsy and leukodystrophies.
Study details, authors and funding
The published paper is titled “A TSPO ligand is protective in a mouse model of multiple sclerosis.” In addition to Wenbin Deng, co-authors include Daniel J. Daugherty, Vimal Selvaraj, Olga V. Chechneva, Xiao-Bo Liu and David E. Pleasure. The research received partial support from the National Institutes of Health, the National Multiple Sclerosis Society, the Feldstein Medical Foundation and Shriners Hospitals for Children (NIH grant numbers R01 NS059043 and R01 ES015988).
This work offers a new avenue for developing treatments that directly target cellular pathways involved in myelin maintenance and repair, complementing existing immunomodulatory therapies for MS. Further preclinical testing is required to identify optimal TSPO-binding compounds with the necessary safety and efficacy profiles for eventual clinical trials.
Contact: Charles Casey – UC Davis
Source: UC Davis press release
Image Source: The brain illustration is credited to the NIH and is available in the public domain.
Original Research: Full open access research for “A TSPO ligand is protective in a mouse model of multiple sclerosis” by Daniel J. Daugherty, Vimal Selvaraj, Olga V. Chechneva, Xiao-Bo Liu, David E. Pleasure and Wenbin Deng in EMBO Molecular Medicine. Published online May 17, 2013 DOI: 10.1002/emmm.201202124