Modulating Cytoskeletal Structure And Cellular Signaling To Target Neuron Cell Membrane Repair

Abstract

Most cells in the human body have the capacity to reseal their cellular membranes following disruption of the lipid bilayer. The cell signaling response regulating membrane repair is dependent on changes in the mechanical tension on the plasma membrane. Increased mechanical tension on the membrane can lead to membrane disruptions remaining open and thus preventing resealing of the membrane. Disruption of these membrane repair processes can result in a number of diseases including muscular dystrophy, Alzheimer's and neurodegeneration. Conversely, if membrane repair can be elevated in striated muscle or neuronal tissues, this response could potentially minimize cell death in neuromuscular diseases and alleviate the progression of these disease states. We have previously shown that tripartite motif (TRIM) 72, also known as mitsugumin 53 (MG53), can increase plasma membrane repair in skeletal and cardiac muscle and in non‐muscle cell types where it is not usually expressed. Our recent results indicate that there are distinct TRIM72/MG53 regulated cellular signaling events that control the membrane repair response in multiple cell types. This observation led us to screen for novel TRIM family proteins that may be able to mediate membrane repair in neuronal cells. We found that TRIM2 transfected cells show an increased capacity for membrane resealing following multi‐photon laser injury and that knockdown of TRIM2 decreases membrane repair. Because TRIM2 is highly expressed in the nervous system and was previously shown to regulate neurofilaments (NFL), the objective of this study is to prove that TRIM2 protects against membrane damage in neurons through regulation of neurofilament ubiquitination and that disruption of TRIM2 or NFL leads to compromised membrane repair and neuron cell death. Through confocal microscopy, we have shown that TRIM2 co‐localizes with NFL in neurons. Following injury to the cell this association is altered, leading to changes in the subcellular localization of TRIM2 and an apparent reorganization of the neurofilament cytoskeleton. Given the extensive expression of TRIM2 in the nervous system, it may represent a good candidate for targeting membrane repair in the treatment of a variety of neurodegenerative diseases.Support or Funding InformationAmerican Heart Association, National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS)‐sponsored T32, and Jain FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.