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Dynamic Nature of the p75 Neurotrophin Receptor in Response to Injury and Disease

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Abstract

Neurotrophins and their respective tropomyosin related kinase (Trk) receptors (TrkA, TrkB, and TrkC) and the p75 neurotrophin receptor (p75NTR) play a fundamental role in the development and maintenance of the nervous system making them important targets for treatment of neurodegenerative diseases. Whereas Trk receptors are directly activated by specific neurotrophins, the p75NTR is a multifunctional receptor that exerts its effects via heterodimeric interactions with TrkA, TrkB, TrkC, sortilin or the Nogo receptor to regulate a wide array of cellular functions. By partnering with different receptors the p75NTR regulates binding of mature versus pro-neurotrophins and activation of different signaling pathways with outcomes ranging from growth and survival to cell death. While the developmental downregulation of the p75NTR has raised questions regarding its role in the mature nervous system, recent data have revealed widespread expression of low levels, a role in synaptic plasticity and adult neurogenesis and upregulation in response to injury or disease. Studies are needed to better understand these processes, particularly in the damaged nervous system, but will be complicated by expression of p75NTR on immune cells including macrophages and microglia that are intimately involved in disease and repair processes. Recent approaches that regulate p75NTR function with small non-peptide ligands have demonstrated potent neuroprotection in models of injury and neurodegenerative diseases that highlight the importance of the p75NTR as a therapeutic target. Future studies hold the promise of revealing a wealth of information on the multifaceted actions of the p75NTR that will inform the design of new neurotrophin-based therapies.

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  1. Department of Neurology, University of North Carolina, CB #7025 6109F Neuroscience Research Building, 115 Mason Farm Road, Chapel Hill, NC, 27599, USA

    Rick Meeker

  2. Curriculum in Neurobiology, University of North Carolina, Chapel Hill, NC, 27599, USA

    Kimberly Williams

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Meeker, R., Williams, K. Dynamic Nature of the p75 Neurotrophin Receptor in Response to Injury and Disease. J Neuroimmune Pharmacol 9, 615–628 (2014). https://doi.org/10.1007/s11481-014-9566-9

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