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Expression and neuro-protective function of latent transforming growth factor binding proteins in the central nervous system of Rodent and Human

Final Activity Report Summary - TRANSFORMING (Expression and neuro-protective function 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 an inactive form together with binding proteins, which also play a role in the activation of TGF-ßs.

With the support of the current Marie Curie International Reintegration grant, we established a molecular biology unit in our Neuromorphological Laboratory, which allowed us to investigate the binding proteins of TGF-ßs called latent TGF-ß binding proteins (LTBPs). We demonstrated that all 4 types of LTBPs are expressed in the brain using RT-PCR technique.

We also produced in situ hybridisation probes for LTBPs and demonstrated that all 4 types of LTBPs have specific distributional patterns, which markedly differ from each other suggesting subtype specific functions. LTBPs were found in the hippocampus, an area first damaged by global brain ischemia. High level of LTBP-3 but not the other 3 types of LTBPs is expressed in the substantia nigra suggesting that TGF-ß affecting the survival of dopaminergic neurons binds to LTBP-3. In motoneurons, LTBP-3 and -4 but not LTBP-1 and -2 are expressed.

Furthermore, the specific expression of LTBP-2 mRNA in orexin neurons, which we found using double in situ hybridization, raises the possibility that LTBP-2 plays a role in the survival of these neurons. These data were also confirmed using double fluorescent immunolabeling using the custom made antibody we produced against LTBP-2.

This finding is particularly important since the loss of hypothalamic orexinergic neurons leads to narcolepsy, a common disorder, which cannot be treated effectively yet. Comparing the distribution of TGF-ßs and LTBPs, we suggest that in the brain, TGF-ß1 binds to LTBP-1, TGF-ß2 binds to LTBP-3, and TGF-ß3 binds to LTBP-3 or LTBP-4. The specific binding relationships allow specific regulatory mechanisms of secretion and activation of different TGF-ßs.

This finding can also be utilised in applied science by directing drugs for survival of specifically affected neuron types in ischemic stroke or neurodegenerative disorders.