The Neurobiology Unit investigates molecular mechanisms involved in neuronal death with the objective of identifying new therapeutic targets for the treatment of neurodegenerative diseases, in particular of Alzheimer's disease. Our team is also affiliated with the Center for Biomedical Research in Neurodegenerative Diseases, CIBERNED. The research is focused into two main lines:
1) Molecular mechanisms of synapse elimination in models of Alzheimer's disease,
2) Mitochondrial epigenetic markers for the early detection of Alzheimer's disease in its preclinical phase. Neurons depend largely on the energy provided by the mitochondria, which in turn are a key element of the apoptotic neuronal death program. Our group investigates the influence of mitochondrial fusion/ fission processes and mitochondrial dynamics on neuronal synapse loss in neurodegenerative disease models. In addition, we investigate the relationship between epigenetics and mitochondrial DNA replication.
Neural synapse loss is a phenomenon that occurs in the initial stages of neurodegenerative diseases such as Alzheimer’s and it is considered to cause the memory deficits characteristic of this disease. However, the mechanisms responsible for synapse elimination during neurodegeneration are still unknown. Our project is focused on two objectives:
1) To identify the molecular mechanisms that cause elimination of synapses in models of Alzheimer's disease, and
2) Search for new mitochondrial biomarkers for the early detection of Alzheimer's disease in its preclinical phase. Experiments within the first objective are directed to identify the molecular mechanisms whereby proteins of the mitochondrial apoptotic death program cause synapse loss. Our hypothesis is that pro-apoptotic proteins reduce the number of neuronal synapses by altering the dynamics and motility of mitochondria. We have previously shown that Neural Pentraxin 1 (NP1) contributes to synaptic damage caused by apoptotic stimuli. In addition, we have demonstrated that NP1 is a pro-apoptotic protein which is increased in dystrophic neurites of brains affected with Alzheimer's disease and that is regulated by the enzyme GSK3 through a neuronal activity dependent signaling pathway of the intrinsic program of apoptotic neurodegeneration. Also, our preliminary results indicate that, once activated the apoptotic program, NP1 is directed to mitochondria and interacts with the pro-apoptotic protein BAX. The experiments included within the second objective are aimed to analyze the regulation of the number of copies of mitochondrial DNA (mtDNA) in patients with mutations in the gene Presenilin1 (PSEN1) in the preclinical phase of Alzheimer's disease. We have previously shown that patients with mutations in PSEN1 have a smaller number of copies of mtDNA long before the onset of disease symptoms. Our hypothesis is that epigenetic modifications caused by the mutation in PSEN1 reduce the replicative capacity mtDNA which in turn causes a decrease in cellular energy required for the neuron to generate or maintain synaptic contacts. The specific objectives that we will investigate in the coming years are:
1) To determine the influence of the gain and loss of function of NP1 in mitochondrial dynamics (fusion / fission) and motility,
2) Identify the relationship between proteins that regulate mitochondrial dynamics with synaptic proteins that interact with NP1 and study the influence of mitochondrial dynamics in synapse loss,
3) Investigate whether silencing of NP1 prevents memory deficits and changes the dynamics and mitochondrial transport in animal models of neurodegeneration.
3) Explore the effect of PSEN1 mutations on epigenetic regulation of mitochondrial DNA. The results will provide new insights into the molecular mechanisms of synapse elimination, and may provide new strategies for therapeutic intervention to prevent the development of the disease.