Neuronal axon degeneration is a hallmark of all neurodegenerative disorders including Alzheimer's, Luo Gehrig's, and Huntington's disease, as well as neural injury (e.g. stroke, traumatic brain injury and spinal cord injury). Moreover, loss f axons and synapses via degeneration is thought to be a main cause of cognitive decline, movement disorders, and paralysis associated with these pathologies. Despite their importance as therapeutic targets, very little is known about the mechanisms underlying axon loss. Beyond pathological situations, axon degeneration is also an important aspect of nervous system refinement during development. One particular aspect of developmental degeneration, that has yet to be discovered in injury-induced degeneration, is the ability to respond to axon derived extrinsic factors. In this proposal we examine whether extrinsic initiators of developmental axon degeneration programs are also used to coordinate injury-induced axon degeneration (also known as Wallerian degeneration) and regeneration. In particular, we examine family members of tumor necrosis factor receptor (TNFR), which are known to be responsible for developmental neuron death and axon degeneration. We present preliminary evidence that these receptors do indeed coordinate injury-induced axon degeneration in tissue culture as well as in mice. These are the first receptors discovered, that when lost, prevent Wallerian degeneration.
In Aim1 we develop an experimental paradigm to rapidly and reproducibly assess axon degeneration in neurons from neonatal and adult mice. This tool will be useful as we continue to explore whether TNFR family members and associated signaling pathways are capable of coordinating Wallerian degeneration in sympathetic and sensory neurons grown in tissue culture (microfluidic devices).
In Aim2, we examine whether extrinsic cues derived from injured axons are capable of expediting developmental axon degeneration. We then leverage this as a bioassay to biochemically characterize these extrinsic factors. Finally, in Aim3 we examine the influence of these pathways on axon degeneration and regeneration in a sciatic nerve axotomy model using mice lacking one or more TNFR family members, their ligands, and/or components of associated pathways. Identifying extrinsic factors that influence Wallerian degeneration has broad implications, not only for understanding how axon degeneration occurs, but also for the range of therapeutic approaches that can be employed to treat pathology-associated degeneration. Our expertise in mouse genetics, developmental neuroscience, cytokine signaling, and biochemical analysis places us in a unique position to delineate mechanisms that have eluded the field for decades.

Public Health Relevance

The proposal examines the molecular basis of injury-induced axon degeneration and regeneration. If successful, this work will inform therapies for a range of neurodegenerative disorders (e.g. Alzheimer's, Parkinson's, Luo Gehrig's Disease) and injury (e.g. spinal cord injury, stroke, traumatic brain injury).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS091617-02
Application #
9125898
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jakeman, Lyn B
Project Start
2015-08-15
Project End
2020-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Virginia
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Cheng, Irene; Jin, Lucy; Rose, Lucy C et al. (2018) Temporally restricted death and the role of p75NTR as a survival receptor in the developing sensory nervous system. Dev Neurobiol 78:701-717
Gamage, Kanchana K; Cheng, Irene; Park, Rachel E et al. (2017) Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons. Curr Biol 27:890-896
Keeler, Austin B; Deppmann, Christopher D (2017) The evolutionary origins of antagonistic neurotrophin signaling. J Cell Biol 216:1223-1225
Gamage, Kanchana K; Cheng, Irene; Park, Rachel E et al. (2017) Death Receptor 6 Promotes Wallerian Degeneration in Peripheral Axons. Curr Biol 27:1250
Keeler, Austin B; Suo, Dong; Park, Juyeon et al. (2017) Delineating neurotrophin-3 dependent signaling pathways underlying sympathetic axon growth along intermediate targets. Mol Cell Neurosci 82:66-75