Honors & Awards
The E. Lucile Smith Award for Excellence in Biochemistry, Department of Biochemistry, The Geisel School of Medicine at Dartmouth (2015)
LLHF Postdoctoral Fellowship, Larry L. Hillblom Foundation (2017-2020)
The Charles B. Carrington Memorial Poster Award, Department of Pathology, Stanford University School of Medicine (2018)
Keystone Symposia scholarship, Keystone Symposia (2019)
The Helena Anna Henzl-Gabor Travel Fellowship, Stanford University (2019)
Bachelor of Science, Kyoto University (2005)
Master of Science, Kyoto University (2007)
Doctor of Philosophy, Dartmouth College (2015)
Marius Wernig, Postdoctoral Faculty Sponsor
Ta-Yuan Chang, Catherine CY Chang, Yohei Shibuya, Elena Bryleva, Stephanie Murphy, Maximillian A Rogers. "United States Patent 9149492 Method for selectively inhibiting ACAT1 in the treatment of alzheimer's disease", Trustees of Dartmouth College, Oct 6, 2015
Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity.
Cell stem cell
Human pluripotent stem cells can be rapidly converted into functional neurons by ectopic expression of proneural transcription factors. Here we show that directly reprogrammed neurons, despite their rapid maturation kinetics, can model teratogenic mechanisms that specifically affect early neurodevelopment. We delineated distinct phases of in vitro maturation during reprogramming of human neurons and assessed the cellular phenotypes of valproic acid (VPA), a teratogenic drug. VPA exposure caused chronic impairment of dendritic morphology and functional properties of developing neurons, but not those of mature neurons. These pathogenic effects were associated with VPA-mediated inhibition of the histone deacetylase (HDAC) and glycogen synthase kinase-3 (GSK-3) pathways, which caused transcriptional downregulation of many genes, including MARCKSL1, an actin-stabilizing protein essential for dendritic morphogenesis and synapse maturation during early neurodevelopment. Our findings identify a developmentally restricted pathogenic mechanism of VPA and establish the use of reprogrammed neurons as an effective platform for modeling teratogenic pathways.
View details for DOI 10.1016/j.stem.2019.04.021
View details for PubMedID 31155484
Acyl-coenzyme A:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer's disease mouse and reduces human P301L-tau content at the presymptomatic stage
NEUROBIOLOGY OF AGING
2015; 36 (7): 2248-2259
Patients with Alzheimer's disease (AD) display amyloidopathy and tauopathy. In mouse models of AD, pharmacological inhibition using small molecule enzyme inhibitors or genetic inactivation of acyl-coenzyme A (Acyl-CoA):cholesterol acyltransferase 1 (ACAT1) diminished amyloidopathy and restored cognitive deficits. In microglia, ACAT1 blockage increases autophagosome formation and stimulates amyloid β peptide1-42 degradation. Here, we hypothesize that in neurons ACAT1 blockage augments autophagy and increases autophagy-mediated degradation of P301L-tau protein. We tested this possibility in murine neuroblastoma cells ectopically expressing human tau and in primary neurons isolated from triple transgenic AD mice that express mutant forms of amyloid precursor protein, presenilin-1, and human tau. The results show that ACAT1 blockage increases autophagosome formation and decreases P301L-tau protein content without affecting endogenous mouse tau protein content. In vivo, lacking Acat1 decreases P301L-tau protein content in the brains of young triple transgenic AD mice but not in those of old mice, where extensive hyperphosphorylations and aggregation of P301L-tau take place. These results suggest that, in addition to ameliorating amyloidopathy in both young and old AD mice, ACAT1 blockage may benefit AD by reducing tauopathy at early stage.
View details for DOI 10.1016/j.neurobiolaging.2015.04.002
View details for Web of Science ID 000355378700004
View details for PubMedID 25930235
ACAT1/SOAT1 as a therapeutic target for Alzheimer's disease
FUTURE MEDICINAL CHEMISTRY
2015; 7 (18): 2451-2467
Alzheimer's disease (AD) is the most common cause of dementia with no cure at present. Cholesterol metabolism is closely associated with AD at several stages. ACAT1 converts free cholesterol to cholesteryl esters, and plays important roles in cellular cholesterol homeostasis. Recent studies show that in a mouse model, blocking ACAT1 provides multiple beneficial effects on AD. Here we review the current evidence that implicates ACAT1 as a therapeutic target for AD. We also discuss the potential usage of various ACAT inhibitors currently available to treat AD.
View details for DOI 10.4155/fmc.15.161
View details for Web of Science ID 000366746000007
View details for PubMedID 26669800
Inhibiting ACAT1/SOAT1 in Microglia Stimulates Autophagy-Mediated Lysosomal Proteolysis and Increases A beta 1-42 Clearance
JOURNAL OF NEUROSCIENCE
2014; 34 (43): 14484-14501
Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) is a resident endoplasmic reticulum enzyme that prevents the buildup of cholesterol in membranes by converting it to cholesterol esters. Blocking ACAT1 pharmacologically or by Acat1 gene knock-out (KO) decreases amyloidopathy in mouse models for Alzheimer's disease. However, the beneficial actions of ACAT1 blockage to treat Alzheimer's disease remained not well understood. Microglia play essential roles in the proteolytic clearance of amyloid β (Aβ) peptides. Here we show that Acat1 gene KO in mouse increases phagocytic uptake of oligomeric Aβ1-42 and stimulates lysosomal Aβ1-42 degradation in cultured microglia and in vivo. Additional results show that Acat1 gene KO or a specific ACAT1 inhibitor K604 stimulates autophagosome formation and transcription factor EB-mediated lysosomal proteolysis. Surprisingly, the effect of ACAT1 blockage does not alter mTOR signaling or endoplasmic reticulum stress response but can be modulated by agents that disrupt cholesterol biosynthesis. To our knowledge, our current study provides the first example that a small molecule (K604) can promote autophagy in an mTOR-independent manner to activate the coordinated lysosomal expression and regulation network. Autophagy is needed to degrade misfolded proteins/peptides. Our results implicate that blocking ACAT1 may provide a new way to benefit multiple neurodegenerative diseases.
View details for DOI 10.1523/JNEUROSCI.2567-14.2014
View details for Web of Science ID 000343658100030
View details for PubMedID 25339759
Transport of LDL-derived cholesterol from the NPC1 compartment to the ER involves the trans-Golgi network and the SNARE protein complex
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2008; 105 (43): 16513-16518
Mammalian cells acquire cholesterol mainly from LDL. LDL enter the endosomes, allowing cholesteryl esters to be hydrolyzed by acid lipase. The hydrolyzed cholesterol (LDL-CHOL) enters the Niemann-Pick type C1 (NPC1)-containing endosomal compartment en route to various destinations. Whether the Golgi is involved in LDL-CHOL transport downstream of the NPC1 compartment has not been demonstrated. Using subcellular fractionation and immunoadsorption to enrich for specific membrane fractions, here we show that, when parental Chinese hamster ovary (CHO) cells are briefly exposed to (3)H-cholesteryl linoleate (CL) labeled-LDL, newly liberated (3)H-LDL-CHOL appears in membranes rich in trans-Golgi network (TGN) long before it becomes available for re-esterification at the endoplasmic reticulum (ER) or for efflux at the plasma membrane. In mutant cells lacking NPC1, the appearance of newly liberated (3)H-LDL-CHOL in the TGN-rich fractions is much reduced. We next report a reconstituted transport system that recapitulates the transport of LDL-CHOL to the TGN and to the ER. The transport system requires ATP and cytosolic factors and depends on functionality of NPC1. We demonstrate that knockdown by RNAi of 3 TGN-specific SNAREs (VAMP4, syntaxin 6, and syntaxin 16) reduces >/=50% of the LDL-CHOL transport in intact cells and in vitro. These results show that vesicular trafficking is involved in transporting a significant portion of LDL-CHOL from the NPC1-containing endosomal compartment to the TGN before its arrival at the ER.
View details for DOI 10.1073/pnas.0807450105
View details for Web of Science ID 000260913500022
View details for PubMedID 18946045