Our primary focus is to understand the cellular and molecular mechanisms driving neurodegeneration, aiming to develop neuroprotective strategies. We study two key molecules, PKD1 (Protein Kinase D1) and Kidins220 (Kinase D interacting substrate of 220kDa), which are vital for neuronal survival. Enhancing these molecules offers neuroprotection, as we have demonstrated. We explore their roles in neurological diseases characterized by neuronal loss, such as acute brain injury {e.g., ischemic stroke (IS)}, and chronic neurodegeneration, including Alzheimer's disease (AD) and Huntington's disease. AD and IS are the leading causes of dementia, affecting around 50 million people worldwide.

In parallel, we study the molecular mechanisms by which PKD influences prostate cancer progression, another scenario where cell survival is critical. Prostate cancer is the second most common cancer and the fifth leading cause of cancer-related deaths among men worldwide.

Our main research lines are:

1.- Investigating the Molecular Mechanisms of Excitotoxicity. Excitotoxicity is a form of neuronal death associated with several neuropathologies, including IS and AD. Preventing excitotoxicity may provide neuroprotection across a broad range of neurological diseases. We have shown that PKD1 protects neurons in highly excitotoxic environments (Nat Comm, 2017). We are now exploring how PKD1 regulates neurodegenerative processes and testing its therapeutic potential in preclinical studies using mouse models of both acute and chronic neurodegeneration. These models involve conditional PKD1 deletion in different brain cell types coupled with multiomics analyses.

2.- Investigating Pathophysiological Mechanisms of KIDINS220 Deficiency. We were the first to clone Kidins220 as the first PKD1 substrate, and are currently studying its role in two rare diseases characterized by KIDINS220 deficits:

-  Idiopathic normal pressure hydrocephalus (iNPH): iNPH is the main form of chronic hydrocephalus in adults, linked to dementia and associated with AD. It involves the accumulation of cerebrospinal fluid, leading to enlarged brain ventricles. Due to the limited understanding of its molecular basis, there are no effective pharmacological treatments. We recently discovered that Kidins220-deficient mice develop hydrocephalus, showing that this protein regulates aquaporin-4 (AQP4), the brain's main water channel (Mol Psychiatry, 2021). We also observed reduced KIDINS220 and AQP4 levels in iNPH patients. Our goal is to develop therapeutic strategies to correct or prevent hydrocephalus in preclinical studies and analyse patient samples to better understand the disease.

-  SINO syndrome: This newly identified rare paediatric condition, caused by pathogenic variants of the KIDINS220 gene, is characterized by spastic paraplegia, intellectual disability, nystagmus, and obesity. Patients with SINO also display ventriculomegaly, similar to Kidins220-deficient mice (Mol Psychiatry, 2021; Genet Med, 2024). In collaboration with international researchers, we aim to study the mechanisms underlying SINO syndrome traits, including hydrocephalus, using human iPSCs and mouse models carrying these variants.

3.- Investigating PKD role in Prostate Cancer. We are also exploring the molecular mechanisms by which PKD influences prostate cancer development and progression. Prostate cancer arises from complex events that ultimately lead to an androgen-resistant phenotype, making it difficult to treat. Advanced prostate cancer is typically managed with chemotherapy, though many tumours develop resistance, resulting in poor outcomes. We have demonstrated that prostate cancer progression is regulated by key signalling pathways, including MAPKs and DUSP1 (Mol Oncol, 2014; Food Chem Toxicol, 2019; Cancers, 2021). More recently, we found that PKD2 activity promotes cell migration and invasion through ERK and Snail (Biochim Biophys Acta Mol Basis Dis, 2024). Our data also show that PKD2 activity increases with tumour malignancy and correlates with higher Snail and ERK expression. We continue to explore PKD's role in other essential processes that drive prostate cancer formation and progression.