Investigating Mechanisms Of Ftld-Tdp Pathogenesis
Frontotemporal lobar degeneration (FTLD) is a devastating dementia disorder that causes profound changes in personality, behavior, and language abilities. Major breakthroughs in the past decade have advanced the understanding of the molecular genetics and pathological mechanisms underlying this disease, in particular the most common subtype, FTLD-TDP. Several causative and risk modifying genes have been identified which implicate defects in protein degradation and RNA metabolism pathways. The work presented here can be split into two main projects. In the first, I examine the physical properties of TDP-43 aggregation, which is a hallmark of FTLDTDP. Specifically, I characterize the role that phosphorylation plays in mediating the aggregation propensity of TDP-43 in a mammalian cell culture system. I further show that TDP-43 aggregates are cleared by the autophagy lysosome and ubiquitin proteasome systems, with the ubiquitin binding adaptor protein, p62/SQSTM1 facilitating this process. In the second project, I sought to characterize the recently identified FTLD-TDP risk factor, TMEM106B. Using cell culture model systems, I demonstrate that TMEM106B overexpression causes specific defects in lysosome size, morphology, and degradative capacity. I also ruled out the effect of a small coding variant associated with the TMEM106B risk allele when the proteins are highly expressed at the same level, indicating that increased TMEM106B levels are the likely cause of defects seen in certain cases of FTLD-TDP. I have also identified a putative degradation pathway implicating lumenal lysosomal enzymes and a membrane bound intramembrane protease, SPPL2a, in the sequential proteolysis of TMEM106B. This pathway may represent a novel therapeutic target for controlling TMEM106B levels in vivo. Overall, my work has contributed significant findings to the field of FTLD-TDP related research and has increased the body of knowledge regarding the cellular and molecular mechanisms that contribute to this terrible disease.
Neurodegeneration; Lysosomes; TMEM106B
Lin, David M.; Brown, William J
Molecular and Cell Biology
Ph. D., Molecular and Cell Biology
Doctor of Philosophy
dissertation or thesis