Aimee Kao, MD, PhD

Assistant Professor
Department of Neurology
akao@memory.ucsf.edu

Despite intensive research efforts, many of the basic mechanisms underlying neurodegenerative diseases remain unclear.  We are tackling this problem by focusing on two genes linked to neurodegenerative disease, progranulin and tau.  By taking advantage of the genetic tractability of C. elegans and the ability to model disease in a dish with patient-derived induced pluriopotent stem cells (iPSCs), we are pursuing studies to understand how mutant forms of these proteins alter fundamental cellular processes such as endocytic trafficking, protein degradation, programmed cell death and stress response.

Progranulin and regulation of programmed cell death kinetics: Disease-related progranulin mutations result in a genetic haploinsufficiency, or production of progranulin protein levels that are approximately half that of normal.  Using the nematode C. elegans and cultured murine cells, we recently discovered that loss of progranulin affects the rate of clearance of apoptotic cells.  One project in the lab is to better understand how progranulin regulates programmed cell death kinetics and how progranulin deficiency leads to neurodegeneration.  Future work will involve understanding the effects of progranulin on microglial function and interrogating the relative roles for granulin versus progranulin.

Pathophysiological Implications of the MAPT A152T mutation: Mutations in the MAPT or tau gene have been associated with several neurodegenerative diseases and tau "tangles" are found in the brains of those afflicated with Alzheimer's Disease.  Recently, a polymorphism in MAPT at position 152 has been described.  We are characterizing the effect of this variant C. elegans and iPSC-derived neurons by observing behavioral alterations as well as biochemical characteristics of tau such as post-translational modification and protein-protein interactions.

Identification of novel regulators of programmed cell death: The core machinery of programmed cell death pathways were first identified in C. elegans. We have recently identified new players in apoptosis as well as new functions for previously identified cell death genes.  Our future work will be to better characterize these cell death effectors, and place them in context of established cellular metabolism.

Primary Thematic Area: 
Neurobiology
Secondary Thematic Area: 
Developmental & Stem Cell Biology
Research Summary: 
Programmed Cell Death and the Pathophysiology of Neurodegenerative Diseases

Websites

Publications: 

MCP-1 and eotaxin-1 selectively and negatively associate with memory in MCI and Alzheimer's disease dementia phenotypes.

Alzheimer's & dementia (Amsterdam, Netherlands)

Bettcher BM, Fitch R, Wynn MJ, Lalli MA, Elofson J, Jastrzab L, Mitic L, Miller ZA, Rabinovici GD, Miller BL, Kao AW, Kosik KS, Kramer JH

Inhibitory Effects of AVEMAR on Proliferation and Metastasis of Oral Cancer Cells.

Nutrition and cancer

Yang MD, Chang WS, Tsai CW, Wang MF, Chan YC, Chan KC, Lu MC, Kao AW, Hsu CM, Bau DT

The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Salazar DA, Butler VJ, Argouarch AR, Hsu TY, Mason A, Nakamura A, McCurdy H, Cox D, Ng R, Pan G, Seeley WW, Miller BL, Kao AW

SLCO3A1, A novel crohn's disease-associated gene, regulates nf-?B activity and associates with intestinal perforation.

PloS one

Wei SC, Tan YY, Weng MT, Lai LC, Hsiao JH, Chuang EY, Shun CT, Wu DC, Kao AW, Chuang CS, Ni YH, Shieh MJ, Tung CC, Chen Y, Wang CY, Xavier RJ, Podolsky DK, Wong JM