MOLECULAR BASIS OF NEURODEGENERATION
Our unit is interested in understanding at the molecular level the processes that trigger neuronal death implicated in several neurodegenerative diseases. We used the neurotrophins and their receptors and their involvement in the degeneration of cholinergic neurons in the basal forebrain, which are the most sensitive population of neurons in Alzheimer’s disease. We use established cell culture lines and primary neuronal cultures, and different molecular biology and microscopy techniques, together with biophysical, structural and computational approaches
The main objectives of the unit are:
- Determine the mechanism of action of p75 receptor in vivo and its role in neurodegenerative diseases. In recent years, our group has revealed the role of the transmembrane domain of p75 in the mechanism of neuronal death and its characterization as a target domain to inhibit p75 activity. We are currently interested in determining the nature and structural architecture of the protein complex triggering neuronal death.
- Determine the mechanism of action of Trk receptor tyrosine kinases to understand the molecular basis of uncontrolled activation that can lead to neurodegenerative diseases besides cancer. In this goal we are using somatic and genetic mutations of TrkA found in i) cancer patients and ii) a rare congenital insensitivity to pain (CIPA) to unravel the molecular mechanism of activation of TrkA both in cancer and neurodegeneration. Our specific objective is included in a broader objective that involves understanding the conformational changes required in a receptor tyrosine kinase to be activated by its ligand.
- As a long-term goal, and joining the objectives 1 and 2, the Unit seeks to determine the connection between neurodegeneration and cancer. Epidemiological studies showed that patients with neurodegenerative diseases have fewer incidences of cancer, and vice versa. However although they seem two antagonistic processes recent studies point that the same signaling pathways and even the same proteins are involved in both processes. For example mutations in the cell cycle, DNA damage repair, degradation of proteins or autophagy machineries induced cell survival and tumor growth in different tissues, but cause the death of postmitotic cells such as neurons and trigger neurodegeneration. Neurotrophin receptors were identified in melanoma (p75) and colon (TrkA) cancer, but play a major role in the development of the nervous system and its dysregulation contributes to the development of neurodegenerative processes in Alzheimer’s disease or Multiple Sclerosis. Our aim is to use the neurotrophic system to unravel the connection between cancer and neurodegeneration.