Línies de recerca
To investigate the role of mitochondrial DNA in synapse elimination and neurodegeneration in genetic models of neurodegenerative diseases
The loss of neuronal synapses is a phenomenon that occurs in the early stages of neurodegenerative disorders. We hypothesize that synaptic neurodegeneration is due to altered mitochondrial DNA (mtDNA) replication and transcription. 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 own transcription strand in the mitochondrial genome. Using this method, we plan to characterize the gene transcription map of the mito-nuclear anterograde signaling pathway. The results will provide new strategies to prevent the development of neurodegenerative diseases.
To study the mechanisms that alter amyloid beta (Aβ) clearance and disposal of dysfunctional mitochondria
Ab accumulation is a primary step of Alzheimer’s disease (AD). Noteworthy, while in early-onset familial AD increased Ab burden mainly results from an enhanced production, recent studies suggest that defective Ab clearance may be the driving force behind sporadic AD, which constitutes the overwhelming majority of human cases. Several processes operating in parallel have been described in Ab clearance; however, the specific factors that contribute to their impairment still remain to be fully defined. Using different experimental models of Alzheimer’s disease, ongoing studies in the lab analize how impaired brain cholesterol homeostasis and enhanced mitochondrial oxidative stress can affect the activity of Ab-degrading enzymes and autophagy, the main cellular catabolic mechanism. Mitophagy and its regulation by mitochondrial cholesterol is also pursued.
Study the role of mitochondrial function in neuroinflammation and amyloid beta (Aβ)-induced cell death
Neuroinflammation is a key pathological feature of Alzheimer’s disease (AD) that results primarily from the presence of chronically activated microglia and astrocytes. However, which factors shift glia phenotype from protective phagocytosis to an inflammatory response are unknown. In experimental AD models, we are evaluating whether different conditions (increased brain cholesterol levels, mild hypoxia) via regulating mitochondrial ROS and autophagy can contribute to stablish a self-generating loop of inflammation and induce necroptosis, thus promoting neurodegeneration.