Harrington A W, Leiner B, Blechschmitt C, Arevalo J C, Lee R, Mörl K, Meyer M, Hempstead B L, Yoon S O, Giehl K M
Department of Cellular and Molecular Biochemistry, Center for Molecular Neurobiology, and Biochemistry Program, Ohio State University, Columbus, OH 43210, USA.
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6226-30. doi: 10.1073/pnas.0305755101. Epub 2004 Mar 16.
The unprocessed precursor of the neurotrophin nerve growth factor (NGF), proNGF, has been suggested to be a death-inducing ligand for the neurotrophin receptor p75. Whether proNGF is a true pathophysiological ligand that is secreted, binds p75, and activates cell death in vivo, however, has remained unknown. Here, we report that after brain injury, proNGF was induced and secreted in an active form capable of triggering apoptosis in culture. We further demonstrate that proNGF binds p75 in vivo and that disruption of this binding results in complete rescue of injured adult corticospinal neurons. These data together suggest that proNGF binding to p75 is responsible for the death of adult corticospinal neurons after lesion, and they help to establish proNGF as the pathophysiological ligand that activates the cell-death program by means of p75 after brain injury. Interference in the binding of proNGF to p75 may provide a therapeutic approach for the treatment of disorders involving neuronal loss.
神经营养因子神经生长因子（NGF）的未加工前体proNGF，被认为是神经营养因子受体p75的一种诱导死亡配体。然而，proNGF是否是一种真正的病理生理配体，能够在体内分泌、结合p75并激活细胞死亡，一直尚不明确。在此，我们报告脑损伤后，proNGF被诱导并以一种能够在培养中触发凋亡的活性形式分泌。我们进一步证明proNGF在体内结合p75，并且这种结合的破坏导致成年损伤皮质脊髓神经元完全获救。这些数据共同表明，proNGF与p75的结合是成年皮质脊髓神经元损伤后死亡的原因，它们有助于确立proNGF为脑损伤后通过p75激活细胞死亡程序的病理生理配体。干扰proNGF与p75的结合可能为治疗涉及神经元丢失的疾病提供一种治疗方法。
