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Distribution and neuroprotective role of Latent Transforming growth factor binding proteins in the central nervous system of Rodent and human

Final Activity Report Summary - TGFB BINDING PROTEIN (Distribution and Neuroprotective Role of Latent Transforming Growth Factor Binding Proteins in the Central Nervous System of Rodent and Human)

The neuroprotective functions of transforming growth factor betas (TGF-ßs) are well established. It has been demonstrated that they play a role in the survival of motoneurons, dopaminergic neurons in the substantia nigra, whose loss results in Parkinson's disease, and also neurons affected by ischemic insult. TGF-ßs are released from the cells in inactive forms along with binding proteins, which also play a role in the activation of TGF-ßs.

In the framework of the current project we investigated the binding proteins of TGF-ßs, called latent TGF-ß binding proteins (LTBPs). We demonstrated that all four types of LTBPs were expressed in the brain. In addition, all four types had specific distributional patterns, which markedly differed from each other suggesting their subtype specific functions. LTBPs were found in the hippocampus, an area that is first damaged by global brain ischemia. High level of LTBP-3, but not of the other three types of LTBPs, wes expressed in the substantia nigra suggesting that TGF-ß affecting the survival of dopaminergic neurons bound to LTBP-3. In motoneurons, LTBP-3 and LTBP-4, but not LTBP-1 or LTBP-2, were expressed. Furthermore, the specific expression of LTBP-2 in orexin neurons raised the possibility that LTBP-2 played a role in these neurons' survival. This was important since the loss of hypothalamic orexinergic neurons led to narcolepsy, a common disorder which could not yet be effectively treated.

Via comparison of the distribution of TGF-ßs and LTBPs we suggested that, in the brain, TGF-ß1 bound to LTBP-1, TGF-ß2 bound to LTBP-3 and TGF-ß3 bound to LTBP-3 or LTBP-4. These specific binding relationships allowed for specific regulatory mechanisms governing the secretion and activation of different TGF-ßs. This finding could also be utilised in applied science through directing drugs for the survival of specifically affected neuron types in ischemic stroke or neurodegenerative disorders.