Antibodies targeting ADAM17 reverse neurite outgrowth inhibition by myelin-associated inhibitors.

in Life science alliance by Nayanendu Saha, Eric Chan, Rachelle P Mendoza, Yevgeniy Romin, Murray J Tipping, Dimitar B Nikolov

TLDR

  • The study identified ADAM17 as the alpha secretase responsible for cleaving the neuronal receptor p75 in a complex with other myelin-associated inhibitors, and demonstrated the ability of inhibitory anti-ADAM17 mAbs to reverse axonal regrowth inhibition.
  • The findings have significant implications for the development of therapeutic strategies for spinal cord injury and may lead to novel treatments for axonal regeneration and recovery.

Abstract

Upon spinal cord injury, axons attempting to regenerate need to overcome the repulsive actions of myelin-associated inhibitors, including the myelin-associated glycoprotein, Nogo-A, and the oligodendrocyte myelin glycoprotein. These inhibitors bind and signal through a neuronal receptor/co-receptor/transducer complex composed of NgR1, Lingo-1, and p75. Consequently, p75 is cleaved by alpha secretase followed by gamma-secretase, triggering downstream signaling that inhibits axonal regrowth. ADAM10 and ADAM17 are both known to function as alpha secretases in neurons. Here we show that ADAM17, and not ADAM10, is the alpha secretase that recognizes and cleaves p75, when it is a part of a 5-component neuron-myelin signaling complex comprising NgR1, Lingo-1, p75, GT1b, and a myelin inhibitor. Importantly, we demonstrate the ability of inhibitory anti-ADAM17 mAbs to abrogate the cleavage of p75 in a neuroblastoma-glioma cell line and reverse the neurite outgrowth inhibition by myelin-associated inhibitors.

Overview

  • This study focuses on understanding the mechanisms of axonal regeneration after spinal cord injury, specifically the role of myelin-associated inhibitors and their interaction with neuronal receptors.
  • The study aims to investigate how the myelin-associated glycoprotein, Nogo-A, and oligodendrocyte myelin glycoprotein inhibit axonal regrowth and how this can be reversed.
  • The primary objective of the study is to identify the alpha secretase responsible for cleaving the neuronal receptor, p75, which is involved in the inhibition of axonal regrowth.

Comparative Analysis & Findings

  • The study found that ADAM17, and not ADAM10, is the alpha secretase that cleaves p75 when it is part of a complex with NgR1, Lingo-1, p75, GT1b, and a myelin inhibitor.
  • The results show that inhibitory anti-ADAM17 mAbs can abrogate the cleavage of p75 and reverse the neurite outgrowth inhibition by myelin-associated inhibitors in a neuroblastoma-glioma cell line.
  • The study demonstrates the important role of ADAM17 in the downstream signaling pathway that inhibits axonal regrowth and highlights the potential therapeutic target for reversing this inhibition.

Implications and Future Directions

  • The findings of this study have significant implications for the development of therapeutic strategies for promoting axonal regeneration and recovery after spinal cord injury.
  • Future studies could investigate the use of inhibitory anti-ADAM17 mAbs as a potential treatment for spinal cord injury and explore the mechanisms by which ADAM17 regulates p75 cleavage and axonal regrowth inhibition.
  • The study also highlights the importance of understanding the complex interactions between neurons and myelin in axonal regeneration and the potential for ADAM17-targeted therapies in central nervous system disorders.
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