Research Summary
Dr. Wong’s research program is designed to understand the molecular mechanisms and identification of new therapeutic targets of neurodegenerative diseases, particularly Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). With discoveries of genes linked to these diseases (mutant APP and PS in familial AD and mutant SOD1, dynactin p150glued ALS4 and ALS2 in familial ALS), his laboratory is taking a molecular/cellular approach, including transgenic, gene targeting and RNAi strategies in mice, to develop models that facilitate our understanding of pathogenesis of disease and the identification and validation of novel targets for mechanism-based therapeutics. Significantly, these mouse models are instrumental for study of disease mechanisms as well as for design and testing of therapeutic strategies for AD and ALS.
Lab
Dr. Wong’s lab is working on the role of Alzheimer’s b-secretase, BACE1 and APP signaling in learning and memory; the role of Alzheimer’s g-secretase, including its function as a tumor suppressor in the skin; and the molecular mechanism of motor neuron disease linked to mutations in dynactin p150glued,SOD1, ALS4 and ALS2 with a focus on alterations in axonal transport.
Lab Website: Philip Wong Lab
Selected Publications
Chow VW, Savonenko AV, Melnikova T, Kim H, Price DL, Li T and Wong PC. “Modeling an anti-amyloid combination therapy for Alzheimer’s Disease.” Science Translational Medicine 2:1-11, 2010
Hu X, Hicks CW, He W, Wong PC, Macklin WB, Trapp BD & Yan R “Bace1 modulates myelination in the central and peripheral nervous system.” Nature Neuroscience, online November 12, 2006.
Laird FM, Cai H, Savonenko AV, Farah MH, He K, Melnikova T, Wen H, Chiang HC, Xu G, Koliatsos VE, Borchelt DR, Price DL, Lee H-K and Wong PC. “BACE1, a Major Determinant of Selective Vulnerability of the Brain to Amyloid-b Amyloidogenesis is Essential for Cognitive, Emotional and Synaptic Functions.” J. Neuroscience 25:11693–11709, 2005.
Cai H, Lin X, Xie C, Laird FM, Lai C, Wen H, Chiang HC, Shim H, Farah M, Hoke A, Price DL, and Wong PC. “Loss of ALS2 function is insufficient to trigger motor neuron degeneration in knockout mice, but predisposes neurons to oxidative stress.” J. Neuroscience 25:7567–7574, 2005.
Ma G, Li T, Price DL and Wong PC. “Aph-1a is the principal mammalian Aph-1 isoform present in g-secretase complexes during embryonic development.” J. Neuroscience 25:192-198, 2005.
Li T, Ma G, Cai H, Price DL, Wong PC. “Nicastrin is required for assembly of presenilin/g-secretase complexes to mediate Notch Signaling, and for processing and trafficking of b-APP in mammals.” J. Neuroscience 23: 3272-3277, 2003.
Wong PC, Cai H, Borchelt DR and Price DL. “Genetically Engineered Mouse Models of Neurodegenerative Diseases.” Nature Neuroscience 5:633, 2002
Subramaniam JR, Lyons WE, Liu J, Bartinakas TB, Rothstein J, Price DL, Cleveland DW, Gitlin JD and Wong PC. “Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading.” Nature Neuroscience 5:301, 2002.
Wong PC, Price DL, Cai H. “The brain's susceptibility to amyloid plaques.” Science 293:1434, 2001.
Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL and Wong PC. “BACE1 is the major b-secretase for generation of Ab peptides by neurons.” Nature Neuroscience 4: 233, 2001.
Chiang P-M, Ling J, Jeong YH, Price DL, Aja S and Wong PC: Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc. Natl. Acad. Sci. USA 107: 16320-16324, 2010. PMID 20660762.
Shyam R, Ren Y, Lee J, Braunstein KE, Mao H-Q and Wong PC: Intraventricular delivery of siRNAs nanoparticles to the central nervous system. Molecular Therapy Nucleic Acids 4, e242, 2015 May 12.
Ling JP, Pletnikova O, Troncoso J and Wong PC: TDP-43 repression of non-conserved cryptic exons is compromised in ALS-FTD. Science 349:650-655, 2015. PMID 26250685.
