Despite being intensively studied, the mechanism whereby the neurotrophin receptor, TrkA, traffics intracellularly is not yet completely understood. Recent data collected in my laboratory indicate that the NGF receptors, p75 and TrkA, cooperatively signal through a novel bridge protein, p62. At its carboxy-terminus p62 possesses a ubiquitin associating domain (DBA) and is capable of binding K63-polyubiquitinated substrates. The amino-terminus of p62 directs its interaction with the proteasome. In addition, p62 serves as a scaffold to recruit TRAF6, an E3-ubiquitin ligase. I hypothesize that p62 binds K63-polyubiquitinated proteins through its UBA domain and shuttles these proteins to the proteasome for degradation. Preliminary findings reveal that TrkA and tau are both TRAF6/K63-polyubiquitinated substrates that interact with p62's UBA domain. Thus, I hypothesize that the neurotrophin signaling and inclusion formation pathway are regulated at the biochemical level by a common protein, p62.
The specific aims for this project period are to test the hypotheses that: 1) p62 serves as an adaptor for TRAFS-ubiquitination of TrkA, thereby regulating receptor trafficking; and, 2) p62 serves to coordinately regulate TrkA trafficking and the inclusion formation pathway in brain. We possess an isogenic p62 knockout mouse and propose to undertake comprehensive characterization of these mice to include: anatomical, behavioral, biochemical, and physiological studies. I hypothesize that as a consequence of p62's absence, K63-poIyubiquitinated proteins such as, TrkA and tau, will progressively accumulate in brain of the p62 knockout mice leading to formation of inclusions along with physiological and behavioral correlates. A number of cutting-edge biochemical, cellular and molecular techniques will be employed in the context of these studies. These findings will fill significant gaps in our understanding of neurotrophin signaling and provide important information required to understand how p62 functions at the cellular/biochemical level. Collectively, information gained from this study will enhance understanding of the role that disturbances in the ubiquitin proteasome pathway plays as a contributing factor to neurodegeneration. Altogether, these efforts will accelerate development and testing of therapeutics to disrupt aggregate formation and treat human neurodegenerative disease(s).
| Seibenhener, Michael L; Wooten, Michael C (2015) Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp :e52434 |
| Du, Yifeng; Seibenhener, Michael L; Yan, Jin et al. (2015) aPKC phosphorylation of HDAC6 results in increased deacetylation activity. PLoS One 10:e0123191 |
| Calderilla-Barbosa, Luis; Seibenhener, M Lamar; Du, Yifeng et al. (2014) Interaction of SQSTM1 with the motor protein dynein--SQSTM1 is required for normal dynein function and trafficking. J Cell Sci 127:4052-63 |
| Seibenhener, M Lamar; Du, Yifeng; Diaz-Meco, Maria-Theresa et al. (2013) A role for sequestosome 1/p62 in mitochondrial dynamics, import and genome integrity. Biochim Biophys Acta 1833:452-9 |
| Seibenhener, M Lamar; Zhao, Ting; Du, Yifeng et al. (2013) Behavioral effects of SQSTM1/p62 overexpression in mice: support for a mitochondrial role in depression and anxiety. Behav Brain Res 248:94-103 |
| Yan, Jin; Seibenhener, Michael Lamar; Calderilla-Barbosa, Luis et al. (2013) SQSTM1/p62 interacts with HDAC6 and regulates deacetylase activity. PLoS One 8:e76016 |
| Seibenhener, Michael L; Wooten, Marie W (2012) Isolation and culture of hippocampal neurons from prenatal mice. J Vis Exp : |
| Jadhav, Trafina; Wooten, Marie W (2009) Defining an Embedded Code for Protein Ubiquitination. J Proteomics Bioinform 2:316 |
| Jiang, Jianxiong; Parameshwaran, Kodeeswaran; Seibenhener, M Lamar et al. (2009) AMPA receptor trafficking and synaptic plasticity require SQSTM1/p62. Hippocampus 19:392-406 |
| Du, Yifeng; Wooten, Michael C; Wooten, Marie W (2009) Oxidative damage to the promoter region of SQSTM1/p62 is common to neurodegenerative disease. Neurobiol Dis 35:302-10 |
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