PLASTICITY AND BEHAVIOR IN ANIMAL MODELS OF TDP-43 PROTEINOPATHIES

LIONEL MÜLLER IGAZ

Cancun

Congreso; The 24th Biennial Meeting of the International and the American Society for Neurochemistry (ISN-ASN); 2013

International and the American Society for Neurochemistry (ISN-ASN)

TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed RNA/DNA-binding protein involved in RNA processing, and structurally belongs to the heterogeneous ribonucleoproteins (hnRNPs) family. TDP-43 serves multiple functions with roles in transcriptional regulation, pre-mRNA splicing and translational regulation, among others. Recent studies demonstrated that TDP-43 is a major disease protein in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). In these and other neurodegenerative disorders, now collectively referred to as TDP-43 proteinopathies, TDP-43 is redistributed from its normal nuclear localization to form cytoplasmic insoluble aggregates. Moreover, pathological TDP-43 is abnormally ubiquitinated, hyperphosphorylated, and N-terminally cleaved to generate C-terminal fragments. We recently generated and characterized new animal models based on the conditional overexpression in the mouse forebrain of human wild-type TDP-43 protein (hTDP-43-WT) or a cytoplasmically-localized form (hTDP-43-NLS), and showed that these mice recapitulate key aspects of FTLD and ALS, including profound neuron loss in specific regions, with corticospinal tract degeneration and a spastic motoric phenotype. However, the physiological role of TDP-43 in behavioral responses has not been thoroughly investigated. Within this framework, we are currently: 1) evaluating if TDP-43 overexpression leads to cognitive deficits, studying the learning and memory performance of these transgenic mice using the inhibitory avoidance task. 2) Studying other behavioral responses in these animals, including locomotor activity, anxiety, hyperactivity, and exploratory behaviors, performing rotarod and open field tests. 3) Assessing changes in plasticity-related pathways using biochemical (immunoblot) and immunohistochemical methods, including well-known gene products involved in neural plasticity (i.e., Arc, c-fos, Zif268, among others). The results from these studies will allow us to shed light onto the physiological roles of TDP-43 in the nervous system, and to address the pathogenic mechanisms underlying TDP-43 proteinopathies, which in turn will be vital to develop new and more effective therapies for these disorders.