Edward S. Giniger, Ph.D.

How do neurons become connected during development? Why do they become disconnected during neurodegenerative disease? And what is the connection between neurodegenerative disease, aging, and dying?

Axon Guidance
For an axon to grow, and grow in the right direction, the effects of molecular cues outside the cell have to be interpreted and channeled by intracellular signaling cascades. How does this happen? Over the past several years, we have been investigating in detail the growth of a single axon in the developing Drosophila wing. By combining molecular and classical genetics, biochemistry, and in vivo live imaging of growing axons with fluorescent bioprobes, we have been led to the entirely novel and unanticipated realization that axon growth is not driven by an explicit, deterministic "motor", but by intrinsic, stochastic fluctuations of the actin cytoskeleton in the axon. The point of external guidance cues is simply to introduce a very small bias to those fluctuations, and it is that bias that gently nudges the growing axon along just the right trajectory to reach its eventual synaptic targets. Ongoing experiments are extending our studies beyond the cytoskeleton to track the contributions of other cell biological processes to axon growth and guidance.

Neurodegeneration
Research in many labs has revealed a host of physiological processes whose dysfunction contribute to neurodegenerative disease: proteostasis, mitochondrial function, innate immunity, cytoskeletal integrity, and above all, aging. But what are the connections between these processes? By studying a simple, endogenous neurodegenerative syndrome in Drosophila – gain- or loss-of-function of the Cdk5/p35 protein kinase – we can now see that these degenerative processes separate into three mechanisms that act essentially in parallel to cause death of neurons. Those three pathways are disruption of the axon cytoskeleton, which leads to axon swelling and fragmentation, inhibition of autophagy, which hyperactivates the innate immune system, causing neurotoxic expression of antimicrobial peptides, and acceleration of the rate of aging, which produces a generalized frailty that sensitizes the nervous system to a whole range of insults. Ongoing efforts focus on identifying the direct links between Cdk5 and each of these pro-degeneration pathways and investigating how their effects can be reduced or eliminated to restore neuron health.

Aging and Lifespan
We have always thought of dying as simply an unfortunate accident; a collapse of biological organization that follows from the progressive declines of aging. However, while examining the relationship between aging and degeneration we unexpectedly came upon evidence that this is not the case. Dying is actually a highly organized process itself, and one that is distinct from aging. Current experiments are identifying the triggers that initiate the process of dying, the regulatory machinery that controls its progression, and the final events that terminate the viability of the individual.

Dr. Giniger received his BS from Yale University (1979) and his Ph.D. from Harvard (1988), the latter studying the yeast transcriptional activator, GAL4, with Dr Mark Ptashne. Dr. Giniger then turned to postdoctoral work with Dr Yuh Nung Jan at UCSF, where he initiated studies of axon guidance in Drosophila. Dr. Giniger continued this work while on the faculty of the Fred Hutchinson Cancer Research Center, in Seattle, WA, prior to joining NINDS as an Investigator in 2004. Dr. Giniger continues to study the mechanism of axon guidance, using in vivo live imaging, biochemistry and genetics to investigate how cytoplasmic signaling pathways interpret external guidance cues to direct axon growth. In recent years, his lab has also begun to investigate adult-onset neurodegenerative diseases. In particular, he seeks to understand how aging interacts with defects in the homeostatic machineries of the neuron, and of the organism, to cause progressive disruption of neural circuits and neuron loss.