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Our group is dedicated to investigating the mechanisms that underly cell survival in two critical systems where this process plays a pivotal role.

Our primary focus is understanding the cellular and molecular mechanisms behind neurodegeneration, with the aim of developing neuroprotective strategies. We concentrate on two key molecules, PKD1 (Protein Kinase D1) and Kidins220 (Kinase D interacting substrate of 220kDa), which are crucial for neuronal survival whose enhancement provides neuroprotection, as we have demonstrated. Our goal is to uncover the roles of these molecules in neurological diseases marked by neuronal loss, such as after acute brain injury (e.g. stroke), or due to chronic neurodegeneration, including Alzheimer's disease (AD) and Huntington's disease (HD). AD and ischemic stroke (IS) are the leading causes of dementia, a progressive syndrome of memory loss affecting approximately 50 million people worldwide.

To complement this focus, we have developed a parallel line of research aimed at understanding the molecular mechanisms by which PKD regulates the development and progression of prostate cancer, another context where cell survival is critical. Prostate cancer is the second most common type of cancer and the fifth leading cause of cancer-related death in men worldwide.

The group's main research lines are:

1.- Investigating the Molecular Mechanisms of Excitotoxicity

Excitotoxicity is a type of neuronal death associated with several neuropathologies, such as IS and AD, and preventing it could offer neuroprotection across a wide range of neurological diseases. We have shown that a constitutively active mutant form of PKD1 provides neuroprotection in highly excitotoxic environments (Nat Comm, 2017). Our research explores how PKD1 regulates neurodegenerative processes, and we are testing the therapeutic potential of PKD1 in preclinical studies using murine models of both acute and chronic neurodegeneration. Our approach includes using mice with conditional kinase deletion in different brain cell types and performing celomic, transcriptomic, metabolomic, and proteomic analyses.

2.- Investigating the Pathophysiological Mechanisms of KIDINS220 Deficiency

We were the first to clone Kidins220 as the first PKD1 substrate and are now studying its role in two rare diseases characterized by KIDINS220 deficits.

-  Idiopathic normal pressure hydrocephalus (iNPH)

iNPH is the major form of chronic hydrocephalus in adults. It is a neurodegenerative disease associated with AD, presenting with dementia and characterized by the accumulation of cerebrospinal fluid, which enlarges the brain ventricles. Due to limited knowledge of its molecular mechanism, there are no pharmacological treatments for iNPH. We recently discovered that Kidins220-deficient mice develop chronic hydrocephalus, demonstrating that this protein regulates the brain's main water channel, aquaporin-4 (AQP4) (Mol Psychiatry, 2021). We also observed a reduction in KIDINS220 and AQP4 levels in the ependymal barrier of brain ventricles in iNPH patients. Our goal is to study neurodegeneration markers in hypomorphic Kidins220 hydrocephalic mice and develop pharmacological and genetic therapeutic strategies to correct or prevent hydrocephalus in preclinical studies. Additionally, we aim to analyse iNPH patient samples to deepen our understanding of this disease.

-  SINO syndrome.

Pathogenic variants of the KIDINS220 gene are associated with a newly identified rare paediatric syndrome called SINO (spastic paraplegia, intellectual disability, nystagmus and obesity). SINO patients exhibit ventriculomegaly similar to that seen in Kidins220-deficient mice (Mol Psychiatry, 2021; Genet Med, 2024). Through an international collaborative effort, we plan to study the mechanisms underlying hydrocephalus and other SINO syndrome traits using human iPSCs and mouse models carrying these pathogenic variants.

3.- Investigating PKD in Prostate Cancer

Our goal here is to explore the molecular mechanisms that regulate Protein Kinase D (PKD) in the development and progression of prostate cancer. This disease arises from a series of complex events that ultimately lead to an androgen-resistant phenotype, significantly complicating treatment. As a result, advanced prostate cancer is typically treated with chemotherapeutic agents. However, many tumours develop resistance, leading to poor prognosis. At the molecular level, we have demonstrated that prostate cancer progression is driven by the regulation of several key signalling pathways, including MAPKs and DUSP1 (Mol Oncol, 2014; Food Chem Toxicol, 2019; Cancers, 2021). More recently, we discovered that PKD2 activity promotes the migration and invasion of prostate cancer cells via its interaction with ERK and Snail, a key transcription factor in epithelial-mesenchymal transition (Biochim Biophys Acta Mol Basis Dis, 2024). Our research also revealed that PKD2 activity increases with the malignancy grade in human tumours, showing a positive correlation with both Snail expression and ERK activity. We are now further investigating PKD's involvement in other critical processes that contribute to prostate cancer formation and progression.