Estrella Gómez Tortosa

March 25, 2024

A Medical Doctor from the Universidad Autónoma de Madrid and a neurologist at the Jiménez Díaz Foundation Hospital since 1997, she has been Head of the Dementia Unit as an Associate Chief since 2009. She expanded her training with one and a half years of stays at the Cognitive Function Department of the National Institutes of Health and the Neuropsychiatric Institute of the University of Illinois in Chicago, and a two-year postdoctoral fellowship at the Alzheimer’s Research Unit of Massachusetts General Hospital (Boston). Her expertise includes clinical and neuropsychological evaluation of neurodegenerative processes, as well as mastery of techniques for neuropathological studies, biological markers, neuroimaging, and genetic data analysis.

Her scientific production addresses clinical-pathological aspects, clinical-genetic correlations, and diagnostic biomarkers in degenerative dementias, including Huntington’s disease, dementia with Lewy bodies, Alzheimer’s disease, and frontotemporal dementias. In 2004, she began following a cohort of cases with familial dementias, which now includes over a thousand probands, collecting DNA, plasma, and cerebrospinal fluid samples to detect new genetic causes and implement diagnostic markers.

Principal investigator in consecutive national projects (SAF-2010-18277, PI14-00099, PI20-00469, Tatiana Pérez de Guzmán el Bueno Foundation Neurosciences Grant 2020, hna Foundation Award 2023). Collaborator in international consortia such as the Amyloid Biomarker Study Group, European Early-Onset Dementia Consortium, and Huntington's Disease MAPS Study. Currently, she is the author/co-author of 80 publications in PubMed and director of two doctoral theses. She received the 2018 Alzheimer’s Award from the Spanish Neurology Society in recognition of her research career in frontotemporal lobar degeneration.

Project Summary and Clinical Relevance

Title: TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism. Journal: Alzheimer's & Dementia.

Alzheimer's disease (AD) occurs through a brain degeneration process where the most influential factors are age (the incidence multiplies by 6 from ages 70 to 80) and familial predisposition. It is evident that there is variable genetic predisposition to AD, but only three causative genes are known to date, involved in amyloid processing and explaining less than 1% of cases.

In this work, a Spanish family with early-onset AD, clearly hereditary (5 out of 8 siblings affected), has been studied clinically and genetically for a decade to identify new genetic causes of the disease. Exome sequencing, along with family segregation study and a functional study, indicates an association of the disease with an unreported mutation p.C168* in the TRIM25 gene, which causes a non-functioning mutated protein. The importance of this work lies in the identification of a new gene as a rare cause of presenile AD by a loss-of-function mechanism, opening new avenues for AD research. The TRIM25 gene presents a new physiopathogenic mechanism in neurodegeneration development, unrelated to the amyloid pathway, as it encodes an E3 ubiquitin ligase enzyme that is selective for the ubiquitination of substrates in the proteasomal or autophagic degradation pathway.