SENIOR HONORS THESES ZOE ADELSHEIM

PI: Michael J. McCarthy, M.D., Ph.D., UC San Diego Department of Psychiatry and Center for Circadian Biology

Contributions of Bipolar Disorder-Associated Risk Genes to Rhythmic Transcription Across the Genome

Sophia Barber

Chengbiao Wu, Ph.D., UCSD School of Medicine, Department of Neurosciences Huntington’s Disease and Alzheimer’s Disease

Impacts on MMP and Lysosomal Speed

Bipolar disorder (BD) is a severe, mood disorder that has genetic risk factors and causes disrupted circadian rhythms, but how BD-associated risk genes regulate circadian rhythms remains undetermined. Presently, four BD-associated risk genes, ARNTL , ANK3, TCF4, and CACNA1C were knocked down using small interfering RNA in neuronal precursor cells derived from induced pluripotent stem cells from healthy donors. Rhythmic gene expression changes were measured using Per2-luc, a circadian reporter and whole-transcriptome RNA sequencing (RNAseq). Knockdown of BD-associated genes altered Per2-luc rhythm properties. RNAseq further revealed that BD-associated gene knockdowns altered rhythmic expression across the genome, including clock genes and other transcripts. Further analysis revealed altered rhythms in transcripts related to pathways previously implicated in BD. Collectively, this work highlights that rhythmic gene expression may be disrupted by variation in BD-associated risk loci. Further understanding of these mechanisms may allow us to better understand the relationship between BD and circadian rhythms.

Julian Bahramipour

PI: Derek Welsbie M.D., Ph.D., Shiley Eye Institute, Department of Ophthalmology

In Vitro Screen for Dominant Negatives of Apoptotic Dual Leucine Zipper Kinase (DLK)

UC San Diego's Senior Honors

Thesis Program allows undergraduate biology majors to work one-on-one with faculty mentors to pursue independent lab research. These are the abstracts of all the exceptional research projects conducted by honors students this past year.

Lysosomes and mitochondria serve critical roles in the cell as the major digestive and energy generating organelles. Lysosomal function has been heavily implicated in major metabolic regulation pathways and, outside of energy production, mitochondria demonstrate key roles in calcium storage and apoptosis decision making. Dysfunction of lysosomes and mitochondria has been linked to the pathogenesis of various neurodegenerative disorders, including Huntington’s disease and Alzheimer’s disease. However, previous models of Huntington’s disease and Alzheimer’s disease have demonstrated incongruent results in regards to the relative lysosome and mitochondrial expression in these conditions. Using primary neuron cultures from E18 mice we studied the distinct changes in lysosomal speed and mitochondrial membrane potential in the BACHD and PSAPP mice models used to demonstrate Huntington’s disease and Alzheimer’s disease respectively. Our results demonstrate increased mitochondrial membrane potential (MMP) in Alzheimer’s disease cortical neurons and decreased lysosomal speed in Huntington’s disease cortical neurons.

Glaucoma is one of the leading causes of irreversible blindness in the world. The hallmark of glaucomatous neurodegeneration is progressive retinal ganglion cell (RGC) apoptosis. RGC cell death is dependent on mitogen activated protein kinase (MAPK) family signaling, notably dual leucine zipper kinase (DLK). In candidate-based screens of DLK dominant negatives, kinase-dead mutants have been shown to ameliorate RGC degeneration. Here, we report a high-throughput, in vitro screen to identify novel dominant negative DLK cDNAs. Efficacious dominant negatives will be utilized to prevent DLK-mediated apoptosis signaling and to reveal novel residues critical to DLK activity.