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Projects. Life and Earth Sciences

Role of the lysosomal protein LAMP2 in the AD-like phenotype induced by HSV-1: Study of the LAMP2 interactome in virus infected neurons

Lead Researcher: María Jesús Bullido Gómez-Heras
Research Centre: Centro de Biología Molecular Severo Ochoa. CSIC-UAM. Madrid.

Abstract: 

María Jesús Bullido Gómez-HerasThe understanding of the pathogenic mechanisms of Alzheimer´s disease (AD) remains a formidable challenge for the scientific community. Mounting evidence point to infectious agents as participants in the neurodegeneration, and herpes simplex virus type 1 (HSV 1) continues consolidating as a major candidate. We have devoted several years to develop neuronal models that simulate different aspects of AD pathogenesis, including oxidative stress and HSV 1 infection, and we have shown that HSV-1 triggers AD-type neurodegenerative events. Functional genomic analysis of the models revealed the lysosomal system as the main pathway altered by HSV-1 in the presence of oxidative stress, with the lysosomal associated membrane protein 2 (LAMP2) among the most modulated genes (unpublished observations).

Recurrent evidences of "female preference" in AD susceptibility and also in HSV-1 infection led us to focus on LAMP2 (X chromosome encoded and therefore with potential sex differential effects) as the strongest candidate to mediate the lysosomal alterations induced by HSV-1. LAMP2 participates in lysosomal cholesterol export and autophagosome maturation, processes essential for lysosome function and reported as deeply altered in neurodegenerative diseases including AD; additionally, two recent reports pointed to LAMP2 as a mediator of virus induced lysosomal dysfunction.

Hence, we hypothesize that interactions between LAMP2 and HSV-1 could be involved in the AD-like phenotype induced by the infection. We propose to investigate their interplay i) by LAMP2 genetic association and HSV serology studies in patients and controls, and ii) by functional and interactome analysis of LAMP2 after HSV-1 infection of neuroblastoma cells and iPSCs derived human neurons.


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