Gomez-Pastor Lab

The principal aim of our laboratory is to understand the molecular pathways that drive neuronal death in Huntington´s disease (HD), an inherited neurodegenerative disorder caused by a CAG triplet repeat expansion within exon-1 of the huntingtin gene (HTT). Mutant HTT protein aggregates and accumulates in virtually all cell types in the body, but it predominantly affects Medium Spiny Neurons (MSNs), a neuronal type located in the striatum. Our main goal is to understand what makes MSNs susceptible to mHTT aggregation and characterize the different stress responses that differentiate these neurons from other cell types in the brain. HD is a devastating neurodegenerative disease for which no therapies are available. Therefore, understanding how mHTT causes neuronal death will contribute to design future therapeutic strategies to hopefully improve the quality of life of patients with this devastating neurodegenerative disease.

Our research:

Our multidisciplinary approach includes quantitative analysis of gene expression, genetic and molecular manipulations of specific pathways, measurement of synaptic function, analyses of protein folding, biochemistry, pharmacology and motor and cognitive behavior. We use primary striatal neurons as well as different HD cellular and mouse models. Our lab is interested in understanding the pathophysiology of HD, its relation with aging-related processes, and the potential commonalities between HD and other neurodegenerative diseases.

Molecular mechanisms that drive MSN dysfunction and death; Heat Shock transcription Factor 1 (HSF1) is responsible for the expression of protein folding machinery and stress protective proteins, synaptic proteins and mitochondrial genes, and it is inappropriately degraded in MSNs in HD. Our hypothesis is that HSF1 degradation contributes to MSNs dysfunction and death during disease progression. We are currently studying how HSF1 is degraded in MSNs in the presence of mHTT.

Therapeutic strategies to intervene HD; Preventing HSF1 degradation is a potential therapeutic strategy to intervene in HD. We are currently implementing pharmacological and genetic approaches to determine the impact of restoring HSF1 levels in mice modelling HD.

Convergent mechanisms of neurodegeneration between HD and other neurodegenerative diseases (NDs); All human proteinopathies have in common the misfolding and aggregation of pathological proteins and the disruption of key cellular processes that subsequently cause cell death. We are currently investigating potential common molecular mechanisms of neurodegeneration across multiple NDs with the final goal to find universal therapeutic targets to simultaneously treat multiple NDs.

HSF1, aging and cognive behavior; We are currently interested in understanding how HSF1's role in the reguation of synaptic proteins affects cognitive processes. In particular we are interested in cognitive behaviors driven by the basal ganglia and how they are affected during aging.