Edward Giniger, Ph.D.
Axon Guidance and Neural Connectivity Section
Building 35, Room 1C1002
9000 Rockville Pike
Bethesda, MD 20892-4478
How do neurons become connected during development? Why do they become disconnected during neurodegenerative disease?
: Research in many labs has revealed a host of physiological processes whose dysfunction contribute to neurodegenerative disease: proteostasis, mitochondrial function, innate immunity, neuronal excitability, axonal integrity, and above all, aging. But what are the connections between these processes? How does their interaction produce the overall outcome of nervous system degeneration? By studying a simple, endogenous neurodegenerative syndrome in Drosophila – gain- or loss-of function of the Cdk5/p35 protein kinase - we can now show that these degenerative processes separate into three, largely parallel mechanisms that interact synergistically to cause death of neurons. First, altering Cdk5 activity disrupts the integrity of the axonal cytoskeleton, leading to axon swelling and fragmentation, and also to loss of the specialized axonal domain where action potentials initiate. Second, altering Cdk5 inhibits autophagy, which in turn hyperactivate the innate immune system, causing release of neurotoxic quantities of anti-microbial peptides. Third, altering Cdk5 accelerates the absolute rate of aging, thus producing an overall organismal fragility, exacerbating the consequences of the other two degenerative pathways and, together, leading to disconnection and death of the neuron. Ongoing efforts focus on identifying the direct links between Cdk5 and each of these pro-degeneration pathways, and in particular on identifying how their effects can be reduced or eliminated to restore neuron health.
Shukla AK, Spurrier J, Kuzina I, Giniger E. Hyperactive Innate Immunity Causes Degeneration of Dopamine Neurons upon Altering Activity of Cdk5. Cell Rep. 2019;26(1):131-144.e4.
Spurrier J, Shukla AK, Buckley T, Smith-Trunova S, Kuzina I, Gu Q, Giniger E. Expression of a Fragment of Ankyrin 2 Disrupts the Structure of the Axon Initial Segment and Causes Axonal Degeneration in Drosophila. Mol Neurobiol. 2019;56(8):5689-5700.
Spurrier J, Shukla AK, McLinden K, Johnson K, Giniger E. Altered expression of the Cdk5 activator-like protein, Cdk5α, causes neurodegeneration, in part by accelerating the rate of aging. Dis Model Mech. 2018;11(3).
Kannan R, Song JK, Karpova T, Clarke A, Shivalkar M, Wang B, Kotlyanskaya L, Kuzina I, Gu Q, Giniger E. The Abl pathway bifurcates to balance Enabled and Rac signaling in axon patterning in Drosophila. Development. 2017;144(3):487-498.
Kannan R, Cox E, Wang L, Kuzina I, Gu Q, Giniger E. Tyrosine phosphorylation and proteolytic cleavage of Notch are required for non-canonical Notch/Abl signaling in <i>Drosophila</i> axon guidance. Development. 2018;145(2).
Related Scientific Focus Areas
Genetics and Genomics
This page was last updated on September 12th, 2019