DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Understanding the Protective Effects of Cellular Prion Protein (PrPC) and Cell Death Protease Inhibition for Treating TBI

Posted Feburary 17, 2017

Richard Rubenstein, Ph.D., State University of New York, Downstate Medical Center

Each year, over 20,000 Service members are diagnosed with traumatic brain injury (TBI)1 and require hospitalization and treatment. TBI is a significant cause of morbidity and mortality among Service members and civilians. TBI often results in central nervous system (CNS) damage and tissue degeneration leading to significant neurological dysfunction. The underlying molecular mechanisms causing the neurological pathology are poorly understood. Calpain, a calcium-activated neuronal protease, has been shown to be associated with several neurodegenerative disorders (i.e. Alzheimer's Disease) and research has recently found it becomes activated within minutes following TBI. Previous studies have also shown that cellular prion protein (PrPC) has neuroprotective functions and during injury, such as TBI, PrPC has been shown to be cleaved by calpain potentially leading to the observed neurodegeneration. With support from a 2010 Defense Medical Research and Development Program (DMRDP) Basic Research Award, Dr. Richard Rubenstein proposed to examine whether TBI-activated calpain cleaves PrPC and whether pharmacologic and/or genetic inhibition of this cleavage would improve upon neuronal survival and functionality thus reducing neuronal dysfunction.

To determine the protective effects of PrPC expression levels and the effect of cell death protease inhibition on neuronal and glial cells, Dr. Rubenstein’s group at the State University of New York Downstate Medical Center conducted in vitro studies using primary murine cerebrocortical mixed cultures (CCM) derived from three mouse lines expressing no PrPC (PrPC knock-out; PrPKO), normal (wild-type; WT), and high (tga20) levels of PrPC. Results from these studies were recently published in Molecular Neurobiology. Results demonstrated that PrPC overexpressing cells (from tga20 mice) provided the most robust neuronal-glial protective effects against both necrotic and apoptotic cell death challenges. PrPC overexpressing CCM lost its neuronal-glial protective effects by 24 hours post-necrotic and apoptosis challenge. Dr. Rubenstein’s group also conducted neuronal and glial biomarker analyses to investigate the effects of PrPC expression levels on the protection of both neurons and astroglial cells against pro-necrotic and apoptotic challenges. Neuronal and glial damage were assessed through the examination of the expression levels of spectrin breakdown products (SBDPs) and glial fibrillary acidic protein breakdown products (GFAP-BDPs or GBDP), respectively. Results showed that both neuronal (SBDPs) and astroglial (GBDP) injury biomarkers were inversely related to the expression levels of PrPC. Moreover, regardless of PrPC expression level, calpain and caspase inhibitors provided further protection against necrotic and apoptotic cell death phenotypes, respectively.

Through this 2010 DMRDP Basic Science Award, Dr. Rubenstein was able to show for the first time that PrPC is protective for both neurons and astroglial cells. Using the observation, that caspase and calpain inhibitors offered further neuro- and astroglial protection, Dr. Rubenstein’s team concluded that induced PrPC expression in conjunction with calpain and caspase inhibitors may provide a platform for future treatment options for TBI that could lead to enhanced neuroprotection and reduced neurodegeneration and thus improve the quality of life for Service members and civilians suffering from TBI. In vivo studies are now ongoing to further examine the influence of experimental TBI on PrPC expression.

Dr. Rubenstein’s research may lead to novel therapeutic strategies for the treatment of TBI that will significantly impact both military personnel and civilians. Additional information about Dr. Rubenstein’s research can be found in Molecular Neurobiology (2016; 53(7):4821-4832).

1 Since 2007. http://dvbic.dcoe.mil/dod-worldwide-numbers-tbi

Publication:

Wang KK, Yang Z, Chiu A, Lin F, and Rubenstein R. 2016. Examining the neural and astroglial protective effects of cellular prion protein expression and cell death protease inhibition in mouse cerebrocortical mixed cultures. Mol Neurobiol 53(7):4821-4832.

Link:

Public and Technical Abstracts: Dual Target-Based Neuroprotection Approach to Treat TBI

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Last updated Friday, February 17, 2017