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Identifier 000430969
Title Ο ρόλος της TDP-43 και σχετιζόμενων πρωτεϊνών σε νευροεκφυλιστικές παθήσεις
Alternative Title The role of TDP-43 and related proteins in neurodegenerative diseases
Author Μπουρμπούλη , Μάρα
Thesis advisor Ζαγανάς, Ιωάννης
Reviewer Παρασκευάς, Γεώργιος
Σίμος, Παναγιώτης
Μήτσιας, Παναγιώτης
Σπανάκη, Κλεάνθη
Τσιβγούλης, Γεώργιος
Πλαϊτάκης, Ανδρέας
Abstract Introduction: TDP-43 (TAR DNA-binding protein-43), encoded by the TARDBP gene, has recently been identified as the molecular link, which connects the, until recently considered, separate entities that currently form the FTD/ALS spectrum. Specifically, TDP-43 is the main component of ubiquitinated inclusions found in both FTD and ALS. The direct causal relationship of TDP-43 with the neurodegenerative process was suggested by the discovery of pathogenic variants in the TARDBP gene, in families with members presenting with FTD/ALS. Furthermore, TDP-43 proteinopathy has been observed in carriers of pathogenic variants in additional genes associated with both FTD and ALS, as well as in patients with an Alzheimer’s disease (AD) subtype, thus demonstrating a more general role of TDP-43 in the neurodegenerative process. The purpose of this dissertation is to investigate TDP-43 proteinopathy in Greek patients with neurodegenerative diseases and in particular: 1. To measure TDP-43 protein levels in the cerebrospinal fluid (CSF) as a candidate diagnostic biomarker for the FTD/ALS spectrum. 2. To detect genetic changes in the TARDBP gene, as well as in other genes associated with FTD/ALS and to evaluate their contribution to the clinical phenotype. 3. To correlate genetic changes not only with the TDP-43 levels in the CSF, but also with the levels of "classical" biomarkers for Alzheimer's disease (AD), i.e. total tau protein (τΤ), its phosphorylated form (τΡ-181) and the β-amyloid peptide with 42 amino acids (Αβ42). Patients and Methods: The study population consisted of 54 patients with FTD, 61 patients with ALS and 14 patients with FTD-ALS, who were diagnosed with the most recent diagnostic criteria, supported by the “classical” AD biomarkers (τΤ, τΡ-181 and Αβ42), in the CSF, to rule out the inclusion of patients with frontal and logopenic variant of AD in the FTD subgroup. The quantitative determination of TDP-43 levels and “classical” biomarkers in the CSF was performed by double-sandwich enzyme-linked immunosorbent assay (ELISA). Patients were screened for pathogenic hexanucleotide repeat expansion (GGGGCC)n in the C9orf72 gene, using the repeat-primed polymerase chain reaction (PCR) method, while C9orf72 (-) patients underwent whole exome sequencing. The levels of biomarkers were compared with a control group of 28 healthy individuals without mental or motor impairment and the genetic changes with an already very wellcharacterized sample of 81 healthy aged adults from Crete. Also, 100 patients from Crete diagnosed with dementia (of the AD type) were tested for pathogenic variants in FTD/ALS genes. Results: Statistically significant higher TDP-43 levels in the CSF were found in all patient groups (FTD, ALS, FTD/ALS), compared to healthy controls. Patients with ALS showed a tendency to have higher CSF TDP-43 levels compared to patients with FTD. Significantly higher levels of τΤ were found in all groups, compared to healthy controls, with the FTD group showing increased levels compared to the ALS group. The levels of τΡ-181 and Aβ42 did not differ significantly among patient groups. ROC analysis showed that the combination of TDP- 43 with τ proteins, as expressed by the formula TDP-43 × τΤ/τΡ-181 has high sensitivity and specificity (> 80%), for separation of ALS/FTD spectrum patients from healthy controls. Genetic analysis revealed pathogenic or likely pathogenic variants in 18.6% (24/129) of patients in the ALS/FTD spectrum. Genes harboring these variants included, in a decreasing order of frequency, the C9orf72, TARDBP, GRN, VCP, SOD1 and FUS genes. The average age of disease onset in patients with the C9orf72 repeat expansion was about 10 years earlier compared to other patients. In 2 patients from Crete initially diagnosed as AD we identified the p.Ile383Val variant. Patients with ALS, either alone or concurrently with FTD, harboring the C9orf72 repeat expansion and the MAPT p.Asp285As change had significantly lower levels of τΡ-181 compared to the other patients. Also, carriers of rare APP variants had lower levels of Aβ42, compared to non-carriers. Conclusions: TDP-43 proteinopathy is a disease entity with significant clinical, biochemical and genetic heterogeneity. It has been traditionally thought to be present in younger patients compared to other neurodegenerative disorders; however, recently it is increasingly recognized among the elderly. The combination of TDP-43 with tau proteins in the CSF, as expressed by the formula TDP-43×τT /τP-181, has high sensitivity and specificity and is therefore a potential biomarker of TDP-43 proteinopathy. The most common gene variant associated with TDP-43 proteinopathy in the Greek population is the C9orf72 repeat expansion with a high frequency of 10,8% (14/129) compared to other European populations and is associated with the disease onset 10 years earlier than the sporadic forms. The variant p.Ile383Val in the TARDBP gene is another common pathogenic variant in the Greek population.
Language Greek
Subject Complications of cirrhosis
Hepatopulmonary syndrome
Επιπλοκές κίρρωσης ήπατος
Ηπατοπνευμονικό σύνδρομο
Κίρρωση ήπατος
Issue date 2020-08-05
Collection   Faculty/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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