Materials Research Science and Engineering Center

Amanda Shilton

"Identifying Key Players in Growth Factor Signaling Defects in Amyotrophic Lateral Sclerosis"

Amanda Shilton*, Mugdha Deshpande, Zachary Feiger, Avital Rodal

Abstract

Amyotrophic Lateral Sclerosis is a neurodegenerative disease that leads to selective death of motor neurons. Mutations in the TAR DNA binding protein (TDP-43), which has thousands of targets in the cell, have been implicated in ALS. The current model of TDP-43 pathology shows that there is dysfunction both when endogenous TDP-43 is lost, as well as when there is a toxic gain of function.

We created an ALS model in Drosophila melanogaster using both loss and gain of function. We found that TDP-43 misexpression results in premature death, larval motility defects and decreased synaptic growth at the neuromuscular junction (NMJ). TDP-43 misexpression also causes reduced Bone Morphogenic Protein (BMP) signaling, which is important for synapse growth. We observed decreased levels of synaptic pMAD (the end product of the BMP pathway responsible for inducing transcription of the genes responsible for growth) although, surprisingly, nuclear pMAD was not affected. There was a shift in the BMP receptor thickveins (Tkv) from the early endosome which is signal permissive to the recycling endosome which is signal non-permissive. We then found that rerouting of BMP receptors by introducing a dominant negative Rab11 partially suppresses the synaptic growth, signaling and crawling defects associated with TDP-43 misregulation.

It however still remains unclear where in the pathway TDP-43 is acting, and which downstream targets are leading to neurodegeneration. Importins are nuclear import/export proteins that allow substrate entry into the nucleus and also may have synaptic functions. It has been previously shown that importin beta-11 mutants exhibit a similar loss of NMJ but not nuclear BMP signaling.

Our current focus is whether or not importin beta-11 acts in the same pathway as TDP-43. We will also look at whether disabling retrograde traffic helps to rescue levels of synaptic pMAD in larvae that are misexpressing TDP-43.

Support: SMURF (Summer MRSEC Undergrad Research Fellowship)