The Neurobiology Unit investigates the molecular mechanisms of neuronal death to identify new therapeutic targets for the treatment of neurodegenerative diseases. Our team is also affiliated with the Center for Biomedical Research in Neurodegenerative Diseases, CIBERNED.
Our research is focused on two main lines: 1) Molecular mechanisms of synapse elimination in models of Alzheimer's disease and 2) Regulation of mitochondrial DNA replication and transcription in genetic models of Alzheimer’s and Parkinson’s diseases.
Neurons depend largely on the energy provided by the mitochondria, which in turn are a key organelle of the apoptotic neuronal death program. Our group investigates the influence of mitochondrial fusion/ fission processes on neuronal synapse loss in models of neurodegeneration. Also, our work aims to identify epigenetic mechanisms that regulate mitochondrial DNA transcription and replication during neurodegeneration.
The loss of neuronal synapses is a phenomenon that occurs in the early stages of neurodegenerative disorders such as Alzheimer's disease and is considered a cause of the memory deficits that are characteristic of this disease. However, the mechanisms responsible for the elimination of synapses during neurodegeneration are not well known.
Our project stems from the hypothesis that mitochondrial DNA (mtDNA) is a central mechanism in the pathological chain of the synaptic neurodegeneration process. The general objectives of our work include:
1) To identify the molecular mechanisms that cause synapse elimination in models of neurodegeneration, and
2) To study transcription and replication of mitochondrial DNA in genetic models of neurodegenerative diseases.
The experiments of the first objective are aimed at studying whether the reduction of neuronal synapses induced by the pro-apoptotic protein Neuronal Pentraxin 1 (NP1) is mediated by mitochondrial quality control systems. The experiments of the second objective are aimed at measuring mtDNA transcription and replication, a study that has been previously limited by the difficulty of accurately measuring the number of mitochondrial genome copies. We have recently developed a method called Selfie-dPCR that allows the quantification in absolute values of the number of mitochondrial transcripts relative to their transcription chain in the mitochondrial genome. Also, in our earlier projects, we found that a decrease in the content of circulating mtDNA in cerebrospinal fluid (CSF) precedes the manifestation of familial Alzheimer's disease, whereas an increase in CSF content of mtDNA is associated with Parkinson's disease in patients with mutations in the LRRK2 gene. Based on these previous findings, we hypothesize that the altered balance between replication and mtDNA degradation evoked by mitochondrial quality control systems determines the type of neurodegenerative process.
The specific objectives to investigate the role of mtDNA transcription and replication in neurodegeneration include:
1) To study the influence of mitochondrial quality control systems on the release of mtDNA in the extracellular space,
2) To measure mtDNA replication and transcription by Selfie-dPCR in genetic models of neurodegeneration and
3) To characterize the gene transcription map of the mitochondrial nuclear anterograde signaling pathway evoked by a pathogenic mutation of the APP gene using the Selfie method coupled to massively parallel sequencing followed by validation with Selfie-dPCR.