Unraveling the molecular basis of abnormal TDP-43 deposition: focusing on therapeutic approaches

• Grant number: 15/17365-7
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): December 01, 2015
• Effective date (End): November 30, 2016
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Suely Kazue Nagahashi Marie
• Grantee: Camila Nascimento Mantelli
• Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Neurodegenerative diseases (NDDs) are highly prevalent and disabling illnesses. Despite the great effort in scientific research, there is a lack of tools to diagnose and treat these diseases. Presence of abnormal protein aggregates in the central nervous system (CNS) is one of the pathological hallmarks of NDDs. The location and extent of these lesions in the CNS, has been used as gold-standard method for post-mortem neuropathological diagnostic criteria of NDDs. Furthermore, this knowledge has brought great contributions to the understanding of the physiopathological mechanisms of these diseases. Transactive DNA-binding protein 43 (TDP-43) plays multiple roles in RNA metabolism in different levels. Its role as a neuropathological hallmark of NDDs has emerged since 2006, after the discovery that TDP-43 was the ubiquitinated protein found in cases of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Recently, it is known that TDP-43 abnormal aggregates can be found in other NDDs, including Alzheimer's disease (AD). It is intriguing the fact that clinically and etiologically distinct diseases share a common neuropathological characteristic, which is the TDP-43 abnormal accumulation. This indicates that distinct biological basis may play role in each disease. This study aims to analyze the transcriptome profile of subjects with different NDDs presenting TDP-43 abnormal aggregation. Two different NDDs will be studied, AD the complex multifactorial disease and the frontotemporal dementia associated to inclusion body myopathy and Paget's diseases of the bone (FTD-IBM-PDB), a rare type of frontotemporal dementia caused by a monogenic mutation in the vasolin-containing-protein gene (VCP gene). For the study of molecular basis of TDP-43 accumulation in AD, we will be using post-mortem human brain tissue. Because FTD-IBM-PDB is a rare disease, we will study neurons derived from mesenchymal stem cells (which in turn will be obtained from a dental pulp of a deciduous tooth) of a patient with VCP mutation. The purpose of our approach is recognizing TDP-43 aggregates related pathways as potential biomarkers, prognostic predictors and therapeutic targets of TDP-43-proteinopathies. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

NASCIMENTO, C.; DI LORENZO ALHO, A. T.; BAZAN CONCEICAO AMARAL, C.; LEITE, R. E. P.; NITRINI, R.; JACOB-FILHO, W.; PASQUALUCCI, C. A.; HOKKANEN, S. R. K.; HUNTER, S.; KEAGE, H.; KOVACS, G. G.; GRINBERG, L. T.; SUEMOTO, C. K. Prevalence of transactive response DNA-binding protein 43 (TDP-43) proteinopathy in cognitively normal older adults: systematic review and meta-analysis. NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, v. 44, n. 3, p. 286-297, APR 2018. Web of Science Citations: 10.