All ETDs from UAB

Advisory Committee Chair

Scott M Wilson

Advisory Committee Members

James F Collawn

Lynn E Dobrunz

Scott E Phillips

Elizabeth S Stzul

Anne B Theibert

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The sorting and degradation of endocytosed cargo by the endosome regulates many cellular functions common to all cells. Neural cells appear to be particularly vulnerable to perturbation in endo-lysosomal transport, and several neurological disorders are caused by a primary deficit in this pathway. In this dissertation, I show that the spontaneously occurring neurological mutation teetering (tn) is a single nucleotide substitution in the endosomal cargo-sorting component hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs/Hrs) that reduces the abundance of HRS. By 3 weeks of age, the tn mice exhibit heightened pain sensitivity, muscle weakness and reduced muscle size. The loss of HRS resulted in structural alterations at the neuromuscular junction (NMJ), including swelling and ultra-terminal sprouting at the motor axon terminals and an enlargement of motor endplate area. These structural changes were accompanied by a reduction in spontaneous and evoked release of acetylcholine, indicating a deficit in presynaptic function at the NMJ. Although we did not observe any axonal loss in the sciatic nerves, there was evidence of both hypermyelinated and dysmyelinated sciatic nerves in the tn mice. These results suggest that HRS has multiple roles in the nervous system and uncover a previously unanticipated requirement for ESCRTs in the maintenance of synaptic transmission.

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