Characterization of Codon Optimized Wild Type TDP-43 Mediated Neurodegeneration in a Drosophila Model for ALS.

TAR DNA Binding Protein-43 (TDP-43) is known to mediate neurodegeneration associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration-ubiquitin (FTLD-U). The exact mechanism by which TDP-43 exerts toxicity in patient brains remains unclear. In a Drosophila model, we have identified robust gain of function phenotypes produced by misexpression of insect codon optimized wild type TDP-43 using the binary GAL4/UAS system, as well as direct promoter fusion constructs with glass promoter. Codon optimized TDP-43 misexpression causes robust phenotypes in the adult eye, wings and bristles in the notum. Compared to human transgenic flies, the codon optimized flies express more protein that forms higher molecular weight species. Both nuclear and cytoplasmic expression of TDP-43 were detected along with cytoplasmic aggregation. Further characterization of the adult retina shows a disruption of the morphology and function of the photoreceptor neurons along with acidic vacuoles that are positive for autophagy markers. Moreover, changes in the protein levels of mTOR signaling pathway substrate were detected upon TDP-43 misexpression. Based on this observation, we believe that TDP-43 has the propensity to form toxic protein aggregates when too much protein is present via a gain-of-function mechanism. Such toxic overload leads to an increase in cellular protein degradation pathways like autophagy. The robust phenotypes seen with TDP-43 misexpression are ideal for genetic screens to identify new modifiers and therapeutic targets. The codon optimized TDP-43 model is a novel and improved model in Drosophila that can be used to better understand the exact disease mechanism of TDP-43 proteinopathies.

Name thesis:degree_name

Neuroscience (Doctoral)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Neuroscience

Grantor

The University of Texas Medical Branch at Galveston

Author dc:creator

• Yusuff, Tanzeen

Advisor dc:contributor.advisor

• Jackson, George R

Committee members dc:contributor.committeemember

• Neugebauer, Volker
• Dineley, Kelly T
• Martinez, Neslihan M
• Kraemer, Brian C
• Wairkar, Yogesh

• TDP-43, amyotrophic lateral sclerosis, frontotemporal dementia

Handle dc:identifier.uri

http://hdl.handle.net/2152.3/871

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/871