The development and maintenance of neural circuits is essential for the formation and function of the nervous system. Circuit development entails axon guidance, synaptic target selection, synapse formation, and synaptic growth and remodeling in response to developmental and environmental inputs. Disrupting these processes in childhood can lead to neurodevelopmental disorders such as mental retardation and autism. In the adult, plasticity mechanisms inducing circuit remodeling likely allow for the encoding of memories, but also contribute to the development of chronic pain and drug addiction. While circuit plasticity is important, it is also essential that circuits be maintained. Disease, trauma,and neurotoxins, including medicines such as chemotherapeutics as well as drugs of abuse such as alcohol and ecstasy, can all trigger an ill-defined axonal degeneration cascade that leads to axonal loss with profound consequences for neurological function. Inhibiting this degeneration program has tremendous potential for the treatment of a host of devastating neurological disorders including Parkinson's disease, Multiple Sclerosis, and neuropathies, but the critical barrier in the field is the lack of knowledge of the key components of the degeneration pathway. Remarkably, a single molecule, the ubiquitin ligase Phr1/Highwire, is a central regulator of both these developmental and degenerative axonal responses. This application explores the function of the Phr1/Highwire ligase, focusing on the recent finding that it is required for normal axonal degeneration in the mouse. The therapeutic potential of inhibiting Phr1 is tested in vivo, while in vitro neuronal culture experiments explore the mechanism of the Phr1-dependent degeneration program. In addition, new Drosophila mutants have been identified that regulate synaptic development and that interact with highwire and its target the MAPKKK Wallenda/DLK. Powerful genetic techniques will be used to analyze these mutants to define molecular pathways controlled by this ligase, allowing for integration of findings in fly and mouse. This innovative, multi-system approach will generate insights into the mechanisms by which neuronal circuits develop and degenerate, and test the therapeutic potential of targeting this essential, evolutionarily conserved ligase and its interaction partners for the treatment of a host of neurological disorders characterized by axon loss.

Public Health Relevance

This research is relevant to public health because it will improve our understanding of how neural circuits form, respond to the environment, and persist throughout life. Defects in these processes can lead to disorders ranging from autism to drug addiction to neurodegeneration. Defining the molecular mechanisms of synaptic growth and stability will identify novel therapeutic candidates for the many devastating neurological disorders where morbidity is largely caused by circuit dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA020812-08
Application #
8628091
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Wu, Da-Yu
Project Start
2005-12-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
8
Fiscal Year
2014
Total Cost
$335,918
Indirect Cost
$114,919
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Zheng, Xingguo; Valakh, Vera; Diantonio, Aaron et al. (2014) Natural antisense transcripts regulate the neuronal stress response and excitability. Elife 3:e01849
Summers, Daniel W; DiAntonio, Aaron; Milbrandt, Jeffrey (2014) Mitochondrial dysfunction induces Sarm1-dependent cell death in sensory neurons. J Neurosci 34:9338-50
Brace, E J; Wu, Chunlai; Valakh, Vera et al. (2014) SkpA restrains synaptic terminal growth during development and promotes axonal degeneration following injury. J Neurosci 34:8398-410
Valakh, Vera; Walker, Lauren J; Skeath, James B et al. (2013) Loss of the spectraplakin short stop activates the DLK injury response pathway in Drosophila. J Neurosci 33:17863-73
Babetto, Elisabetta; Beirowski, Bogdan; Russler, Emilie V et al. (2013) The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction. Cell Rep 3:1422-9
Kim, Sungsu; Naylor, Sarah A; DiAntonio, Aaron (2012) Drosophila Golgi membrane protein Ema promotes autophagosomal growth and function. Proc Natl Acad Sci U S A 109:E1072-81
Shin, Jung Eun; DiAntonio, Aaron (2011) Highwire regulates guidance of sister axons in the Drosophila mushroom body. J Neurosci 31:17689-700
Tian, Xiaolin; Li, Jing; Valakh, Vera et al. (2011) Drosophila Rae1 controls the abundance of the ubiquitin ligase Highwire in post-mitotic neurons. Nat Neurosci 14:1267-75
Daniels, Richard W; Miller, Bradley R; DiAntonio, Aaron (2011) Increased vesicular glutamate transporter expression causes excitotoxic neurodegeneration. Neurobiol Dis 41:415-20
Graf, Ethan R; Heerssen, Heather M; Wright, Christina M et al. (2011) Stathmin is required for stability of the Drosophila neuromuscular junction. J Neurosci 31:15026-34

Showing the most recent 10 out of 21 publications