Year: 2017
Type: dissertation
Abstract: Transactivation response DNA binding protein (TDP-43) is a DNA/RNA binding protein involved in the regulation of thousands of genes via nucleotide binding and alternative splicing of pre-mRNAs.In 2006, it was identified as the constituent protein of ubiquitin-positive protein inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FLTD), leading to the description of these diseases as TDP-43 pathologies.Mutations in TDP-43 have been found to cause familial ALS and FTLD, but the majority of these cases are sporadic, and thus the disease-related protein aggregates only contain wild-type (WT) TDP-43.Understanding how wild-type, or non-mutated, forms of TDP-43 can contribute to disease is important in understanding disease mechanisms and for creating new therapeutic strategies.This research first focuses on the characterization of a hemizygous transgenic mouse model that overexpresses human WT TDP-43 in neurons.This model was then used to investigate the effects of neuronal TDP-43 overexpression on non-neuronal cells, synaptic maintenance, and amino acid homeostasis.We found that this mouse model may be a model of the spectrum of TDP-43 pathologies rather than one disease.TDP-43 overexpression leads to amino acid imbalance, astrocyte dysfunction, and downregulation of synaptic proteins.These cellular and molecular changes were ameliorated by treatment of the mice with the tyrosine kinase inhibitors (TKI) nilotinib and bosutinib.There is no cure for TDP-43 pathologies and the only FDAiv approved drugs for ALS, riluzole and edavarore, have limited benefits.This work shows that a different family of drugs, TKIs, may be useful for the treatment of TDP-43 pathologies.v ACKNOWLEDGEMENTS I would like to thank my mentors, Charbel Moussa and Brent Harris, for all of the support and guidance they provided for me over the last five years.None of this would have been possible without you there to teach me and help me become a better scientist.
Author: Lanier Heyburn
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2761409347