Our group is focused on understanding cellular and molecular mechanisms underlying neurodegeneration searching for neuroprotection strategies. We study PKD1 (Protein Kinase D1) and Kidins220 (Kinase D interacting substrate of 220kDa), two molecules we have shown to be key for neuronal survival and that potentiate neuroprotection. We work on elucidating the role of both proteins in neurological diseases suffering neuronal loss after acute brain damage, such as stroke, or by chronic neurodegeneration, such as Alzheimer´s, disease (AD) or Huntington´s disease. AD followed by ischemic stroke (IS) are the main cause of dementia, a progressive memory loss syndrome affecting nearly 50 million people worldwide.
Our principal research lines are:
1.- To investigate the molecular mechanisms of excitotoxicity, a type of neuronal death occurring in numerous neuropathologies, such as IS o AD, and whose prevention may confer neuroprotection in a broad range of neurodegenerative conditions. We have shown that a constitutively active mutant form of PKD1 confers neuroprotection in highly excitotoxic environments (Nat Comm, 2017). We pursuit to analyse PKD1 regulation of neurodegenerative processes and assay the therapeutic potential active PKD1 in preclinical studies using acute and chronic neurodegeneration mouse models. For our studies we employ mice with conditional deletion of the kinase in different brain cellular lineages, and celomic, transcriptomic, metabolomic and proteomic analysis.
2.- To investigate the pathophysiological mechanisms associated with KIDINS220 deficiencies. We cloned Kidins220 as the first PKD1 substrate, and we are investigating two rare diseases with KIDINS220 deficits.
- Idiopathic normal pressure hydrocephalus (iNPH). The major form of chronic adult hydrocephalus is iNPH, a neurodegenerative disease associated with AD and dementia, characterized by cerebrospinal fluid accumulation and ventricular enlargement. Unfortunately, iNPH has no pharmacological treatments due to the little knowledge of the underlying molecular mechanisms. We have recently discovered that hypomorphic Kidins220 mice present chronic hydrocephalus, demonstrating that Kidins220 regulates the major brain water channel, aquaporin-4 (AQP4) (Mol Psychiatry, 2021). In addition, we have observed that KIDINS220 and AQP4 expression is reduced at the ependymal barrier of cerebral ventricles in iNPH patients. We aim to study neurodegeneration hallmarks in hydrocephalus Kidins220 deficient mice and to develop pharmacological and genetic therapeutic approaches to correct or prevent hydrocephalus in preclinical studies. Finally, one major interest for us is the analysis of samples from iNPH patients to improve our knowledge of this poorly studied disease.
- SINO syndrome. Pathogenic variants of KIDINS220 gene are associated with a novel rare syndrome in children named SINO (spastic paraplegia, intellectual disability, nystagmus and obesity). SINO patients show ventriculomegaly that resembles that of Kidins220 deficient mice. We plan to study the mechanisms underlying hydrocephalus and other SINO syndrome traits in mice and human iPSCs carrying these pathogenic variants in an international collaborative framework.