Dr. Susan Ackerman at UCSD focuses her research on the molecular mechanisms involved in maintaining homeostasis during development and aging of the mammalian brain. She is particularly interested in how altered translation elongation, caused by ribosome stalling, affects neuronal function and survival.
In her recent paper, “Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation” Dr. Ackerman addresses the issue of determining the signaling pathways initiated by ribosome stalling. In order to study these signaling pathways, Dr. Ackerman made use of the mutant mouse line, C57BL/6J-Gtpbp2nmf205-/- , which have stalled neuronal elongation complexes. She first performed gene expression studies on isolated cerebella from control B6J mice and mutant B6J-Gtpbp2nmf205-/- mice at 3- and 5-weeks of age. Dr. Ackerman found a total of 910 and 325 differentially regulated genes in the 5-week old and 3-week old mutant cerebellum, respectively. Since ribosome stalling, as seen in these mutant mice, has been shown to cause neurodegeneration, she next performed Kegg pathway analysis and Ingenuity Pathway analysis on the differentially regulated genes and found enhanced inflammation/immune pathways. Interestingly, when these differentially regulated genes were compared to activated genes in microglia and astrocytes from mice models of amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease, Dr. Ackerman found overlaps with 150 and 60 genes expressed in the activated microglia and astrocytes, respectively.
Further analysis of the differentially expressed genes revealed upregulation of activating transcription factor 4 (ATF4), which is an important component of the integrated stress response. Next, Dr. Ackerman studied the activation of ATF4 in the mutant mice and found ATF4 target genes were upregulated in both cerebellum and hippocampal tissue. Additional analysis revealed that the activation of ATF4 was dependent on GCN2 kinase, which is activated by amino acid deprivation.
Dr. Ackerman then proceeded to study the effects of the GCN2-ATF4 pathway on neuron survival. To do this, she compared the progression of neurodegeneration induced by ribosome stalling in two mutant mice strains. The first was the B6J-Gtpbp2nmf205-/- strain described earlier, and the second was the B6J-Gtpbp2nmf205-/-;Gcn2-/- strain. Dr. Ackerman found that the B6J-Gtpbp2nmf205-/-;Gcn2-/- strain showed increased granule cell death as compared to the B6J-Gtpbp2nmf205-/-. Additionally, the B6J-Gtpbp2nmf205-/-;Gcn2-/- strain showed extensive cell death within the CA1 region of the hippocampus which was not present in the B6J-Gtpbp2nmf205-/- strain.
Dr. Ackerman’s paper, “Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation” provides a very detailed examination of the ribosome stalling triggered GCN2-AFT4 signaling pathway.
To hear more about Dr. Susan Ackerman’s research, please attend her talk on Tuesday, November 29, 2016 at 4pm in the CNCB Marilyn G. Farquhar Seminar Room.
Oscar Gonzalez is a first-year graduate student in the neurosciences graduate program and a member of Dr. Maxim Bazhenov’s lab. He is interested in the mechanisms leading to hypersynchronous activity in the brain, and the origin of resting state infra-slow fluctuations.