Javier Sánchez will present his doctoral thesis on Thursday, July 14th

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Javier Sánchez will present his doctoral thesis on Thursday, July 14th

Javier Sánchez Ruiz de Gordoa, predoctoral researcher of the Neuroepigenetics Unit of Navarrabiomed, will be sitting his viva for his doctoral thesis from the Public University of Navarra next Thursday, July 14th at 4 pm in the Assembly Hall of Navarrabiomed. 

The doctoral work, which is entitled “Progressive Supranuclear Palsy: clinical-pathological correlation and approach to the pathogenic role of microglia”, has been developed at the University Hospital of Navarra and Navarrabiomed under the direction of Elena Erro Aguirre, Maite Mendioroz Iriarte and Mª Victoria Zelaya Huerta.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease which manifests clinically as an atypical Parkinsonism. The deposits of tau protein in neurons and glial cells are its pathological basis and is the most common primary tauopathy. The ultimate diagnosis is neuropathological and, in recent years, progress has been made in the definition of more sensitive and specific clinical diagnostic criteria and in the identification of potential biomarkers.
The hypothesis of this doctoral thesis is that there is a correlation between the different density and distribution of tau protein deposits in the different structures of the brain and the phenotypic expression of PSP. In turn, this clinical expression could be influenced by the interaction of the tau protein with other neuronal protein deposits. It is further proposed that the activation of microglia may play a role in the pathophysiology of the disease.

Research development and results

For research development, three works have been prepared that form a thematic unit. In the first of them, a descriptive cross-sectional study of the clinical-pathological characteristics of the series of 34 cases of PSP of the Navarrabiomed biobank, patients who died between 2005 and 2017, is carried out, and the deposits of the tau protein are compared between the clinical phenotypes resulting from the retrospective application of different clinical diagnostic criteria.  In the second work, cases presenting a coexpression of the tau protein and alpha-synuclein are described and the distribution of the deposits in the substantia nigra (SN) and the Locus Coeruleus is studied using double immunohistochemistry and immunofluorescence techniques. In the third work, a descriptive observational study is carried out comparing the expression of a candidate gene, TREM2 (Triggering Receptor Expressed in Myeloid cells type 2), related to inflammation and microglial activation, in samples of SN from 24 cases of PSP and controls without neuropathology, and the correlation between gene expression and tau protein deposits is analysed.

The results obtained show that the application of the new criteria for the diagnosis of PSP of the Movement Disorders Society decreases the phenotypic variability and, together with other limiting factors such as sample size, conditions the loss of differences in the cortical tau load identified between the resulting phenotypes after the application of other previous classifications. On the other hand, the coexpression of alpha-synuclein (Lewy bodies) and tau protein deposits in the same dopaminergic neurons of the SN of patients with PSP is described for the first time. In addition, it is identified that the TREM2 gene is overexpressed in the SN of patients with PSP with respect to controls and that this expression correlates directly with tau protein deposits in the SN suggesting that TREM2-mediated microglial activation participates in the pathophysiology of the disease. 

Dissemination of results 

The work carried out has led to several scientific publications: in 2022, in the journal Frontiers in Neurology, Is the phenotype designation by PSP-MDS criteria stable throughout the disease course and consistent with tau distribution?, in 2020 in the journal Movement Disorders, Microglia-Related Gene Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) Is Upregulated in the Substantia Nigra of Progressive Supranuclear Palsy and in 2015 in the journal Frontiers in Neuroanatomy, Midbrain catecholaminergic neurons co-express α-synuclein and tau in PSP. 

In addition, the preliminary and definitive results have been disseminated at several national and international congresses in the area of Neurology and Pathological Anatomy such as the annual meeting of the Spanish Society of Neurology (in 2013, 2017 and 2019), the International Conference on Frontotemporal Dementias in 2016, the European Congress of Neuropathology (in 2016 and 2018) or the annual meeting of the MDS in 2018.