The Role of Polyubiquitination in Nerve Growth Factor Signaling and its Alteration in Alzheimer’s Disease

Abstract

Nerve growth factor (NGF) is a neurotrophin regulates survival and differentiation of neurons. To execute its antiapoptotic function, NGF binds to selective receptor TrkA and non-selective receptor p75NTR, leading to TrkA dimerization and autophosphorylation, which recruits downstream signaling proteins, including phospholipase C-1, Shc, FRS2 and phosphoinositol 3-kinase (PI3K)/Akt. Here we demonstrate that NGF stimulation leads to both p75NTR and TrkA polyubiquitination resulting in neuronal cell survival. We also show that both p75NTR and TrkA undergo TRAF6-mediated polyubiquitination with Lys-63(K63) ubiquitin chains on NGF stimulation, which is required for activation of downstream cell signaling such as PI3K/Akt pathway and mitogen-activated protein kinase (ERK/MAPK) pathway. TRAF6, an ubiquitin E3 ligase, interacts with scaffold protein p62 on NGF stimulation and promotes polyubiquitination of p75NTR and TrkA. Amyloid beta (Aβ) protein is the primary proteinaceous deposit found in the brains of patients with Alzheimer's disease (AD). Evidence suggests that Aβ plays a central role in the development of AD pathology. We revealed that both p75NTR and TrkA polyubiquitinations are impaired in the presence of Aβ in vitro or in AD brains. Interestingly, the nitrotyrosylation of TrkA was increased in AD hippocampus and this might be an explanation for reduced phosphotyrosylation and ubiquitination of TrkA. Furthermore, In AD brain, the matrix metalloproteinase-7 (MMP-7), which cleaves iii proNGF to produce mature NGF, was also reduced, thereby leading to the imbalance between pro-NGF and NGF and eventually activating cell apoptosis.