• How do axons degenerate?

    The degeneration of axons is a widespread event in the developing nervous system, and also considered to be a hallmark of nervous system injury and neurodegenerative disease. Remarkably, the underlying molecular mechanisms that execute axon degeneration remain poorly understood in any context, making the development of efficacious treatments to block axon loss challenging.

    We are interested in identifying genes required for injury-induced axon degeneration (axon death). It is important to delineate axon death signaling, because it is a shared pathway in injury and disease, and conserved throughout evolution. Injury activates axon death signaling in the distal, from the soma separated axon. While severed wild type axons undergo axon death within 1 day, and resulting debris is cleared within 3-5 days, axons defective in axon death remain preserved for the life span of the fly, and weeks in mice. We study axon death signaling in Drosophila, and are able to use highly sophisticated tools with which to observe morphology and function of axons and their synapses:

    Morphology: Axon death can be observed in injured axons side-by-side of uninjured controls of sensory neurons in the same nerve bundle in the wing. It allows for visual resolution with previously unprecedented depth.

    Schematic wing containing two GFP-labeled sensory neuron clones, field of axon observation (black box), and examples of wild type and axon death mutants.

    Function: The functional preservation of severed, axon death defective axons and their synapses can be measured in specific sensory neurons required and sufficient for antennal grooming. Antennal ablation results in the removal of somas, whereas axons & synapse remain in the CNS: they are activated by optogenetics, and the resulting antennal grooming behavior serves as an in vivo readout for functional preservation.

    Optogenetics combined with grooming as a behavioral readout to measure functional preservation of axons and their synapses.

  • How are axons maintained?

    Neurons with long axons are a vulnerable bottleneck for the nervous system. Axonal transport alone cannot meet the need for sustained maintenance and energy demand of a very long axon and its synapse far from the neuronal soma. Recently, a growing number of evidences supports the notion that the survival of an axon also depends on local intrinsic, as well as glial-derived extrinsic support mechanisms. However, we still know very little about these survival mechanisms.

    We are interested in identifying both intrinsic and extrinsic axonal survival mechanisms. It is important to understand those mechanisms, because the attenuation thereof has been linked to a variety of human axonopathies. Axons and their synapses defective in axon death, which were separated from their somas, remain morphologically and functionally preserved for weeks. They provide an ideal sensitized background with which to identify local axonal intrinsic, and glial-derived extrinsic survival mechanisms. We will use the wing and head of Drosophila to identify novel survival mechanisms important for morphology and function specifically for axons and their synapses.

  • How do neurons degenerate?

    Mature, circuit-integrated neurons promote survival at all costs by employing multiple strategies to prevent neuronal cell death (neurodegeneration). Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme for reduction-oxidation reactions, and cosubstrate for NAD+ consuming enzymes. NAD+ concentrations are crucial for neuroprotection: while high levels promote neuroprotection, low levels induce neurodegeneration. Why NAD+ concentrations drop in neurodegenerative conditions, and how NAD+ depletion triggers neurodegeneration, remains completely unknown.

    We would like to understand how neurodegeneration is triggered by NAD+ depletion. Our lab is able to induce the expression of an NAD+-consuming enzyme in a subset of neuronal cells (clones), thereby depleting NAD+, which culminates in rapid neurodegeneration in vivo. To gain insights into the underlying mechanisms, we performed an unbiased screen to isolate candidates that, when mutated, suppress neurodegeneration induced by NAD+ depletion. We are currently characterizing this novel type of neuronal cell death, as well as the underlying signaling mechanism which executes neurodegeneration.

    Rapid depletion of NAD+ in a subset of photoreceptor neurons results in neurodegeneration, which is blocked by a recently isolated suppressor.