Objective
Neurodegenerative disorders of the central nervous system (CNS) such as Alzheimer's (AD) and Parkinson's diseases are devastating and ever increasing health problems for which there is no effective treatment. Neurotrophins prevent neuronal degeneration produced by injury or normal aging and these factors are currently being tested in clinical trials for treatment of neurodegenerative disorders. Because neurotrophins do not penetrate the blood-brain barrier, they would have to be administered into the brain ventricles for the treatment of AD. However, neurotrophins, in particular brain-derived neurotrophic factor (BDNF) are relatively abundantly expressed in normal brain and only slightly reduced in AD brain 1 (for references see p.7) suggesting that the problem in degenerative disorders is not the lack of neurotrophins but their compromised signaling capacity. Treatments that enhance the ability of endogenous neurotrophins to activate their receptors would therefore represent a new therapeutic approach in the treatment of these devastating disorders.
TrkB, the receptor for BDNF and neurotrophin-4, is alternatively spliced into several different types of receptor isoforms. Extracellularly we have recently found two variants, L1 and L0, which lack two or all three of the leucine-rich domains and do not bind any neurotrophins2. Intracellularly there are the full-length, tyrosine kinase (TK) domain-containing form TK(+) and the truncated form TK(-)3. These isoforms are identical in their extracellular and transmembrane domains, but in place of the intracellular TK domain, TK(-) forms only contain short unique intracellular tail regions. Both receptor variants bind neurotrophins, but only TK(+) can activate intracellular signal transduction. TK(-) forms may influence the function of neurotrophins in several ways. First, by restricting the diffusion of neurotrophins from cerebral ventricles and within parenchyma. Second, by mediating internalization of neurotrophins into non-neuronal cells and thereby reducing the amount of neurotrophins available to neurons18. Third, TK(-) form acts as a dominant negative receptor preventing signal transduction upon heterodimerization of the two splice variants in neurons that coexpress both variants4. Indeed, the ability of BDNF to activate trkB signaling in cortex is decreased during postnatal development concomitantly with a dramatic increase in the relative abundance of the trkB-TK(-) form5 suggesting that trkB-TK(-) may limit the ability of BDNF to activate trkB receptors in-vivo. Finally, it has recently been suggested that TK(-) form may mediate a signal of its own6.
We propose that the alternative forms of trkB could significantly reduce the neuronal responsiveness to neurotrophins in adult brain thereby sensitizing neurons to degeneration. The aim of this project is to investigate the role of neurotrophin receptor splice variants in neurodegeneration and trkB splicing in AD brain. We will create in-vitro and in-vivo models using adenoviral gene transfer and transgenic mice to investigate extent alternatively spliced isoforms of trkB are involved in neurodegeneration. Using the yeast two-hybrid assay and site-directed mutagenesis, we will identify molecules that specifically interact with different splice variants. We will further investigate the molecular mechanism of splice site selection in the TrkB gene and identify cellular factors and elements within the gene that are involved in this process. Our final goal is to identify targets for new drug therapies that would enhance the ability of endogenous neurotrophins to activate their receptors.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- medical and health sciences basic medicine neurology dementia alzheimer
- medical and health sciences medical biotechnology genetic engineering gene therapy
- medical and health sciences basic medicine neurology parkinson
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Coordinator
70211 KUOPIO
Finland
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