Signaling by growth/differentiation factor 5 through the bone morphogenetic protein receptor type IB protects neurons against kainic acid-induced neurodegeneration

Abstract

Growth/differentiation factor-5 (GDF-5), a member of the transforming growth factor-beta (TGF-β) superfamily, has been shown to protect rat dopaminergic neurons against insult both in embryonic neuronal culture and in Parkinson's disease models. However, whether GDF-5 exerts neuroprotective effects in hippocampal neurons is unclear. Here, we show that both mRNA levels and protein levels of GDF-5 are decreased in the mouse hippocampus upon kainic acid (KA) treatment. KA induced dramatic neuronal loss specifically in the cornu ammonis 1 (CA1) and CA3 areas of the mouse hippocampus, while intracerebral infusion of GDF-5 prevented this neuronal loss. The neuroprotective effects of GDF-5 were recapitulated by constitutively active bone morphogenetic protein type IB receptor (BMPRIB-CA) and could be blocked by BMPRI kinase inhibitor LDN-193189. Furthermore, the neuroprotective effects of GDF-5 were mediated through the prevention of apoptosis, which was indicated by terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining and reduced cleaved caspase 3 expression level. Thus, we conclude that GDF-5 protects hippocampal neurons against KA-induced neurodegeneration by signaling through BMPRIB, suggesting a therapeutic potential for GDF-5 in neurodegenerative diseases.

Keywords: Bone morphogenetic protein type IB receptor; Growth/differentiation factor-5; Hippocampal neuron; Kainic acid; Neurodegenerative disease.