Over the past 20 years, I have developed two major programs in the field of neurodegenerative diseases focused on molecular mechanisms of Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS) and on defining the molecular participants potentially amendable to therapeutic interventions using molecular biological approaches, including transgenic and gene knockout strategies. Over the past decade, we assessed BACE1 and γ-secretase, enzymes required for the generation of β-amyloid, as therapeutic targets for AD. We are currently developing next generation set of mouse models of AD for mechanistic studies as well as for testing therapies. My laboratory also has built mouse models of motor neuron disease for the study of Amyotrophic Lateral Sclerosis (ALS). More recently, my group has generated mouse models of TDP-43 in efforts to unravel the physiology and pathophysiology of this RNA binding protein implicated in ALS and Frontotemporal dementia (FTD). We recently discovered a novel function of TDP-43 in repression of splicing of non-conserved cryptic exons and disclosed that this role of TDP-43 is compromised in brains of ALS-FTD. We currently are embarking on identifying functional biomarkers and validating repression of cryptic exons as a therapeutic target for ALS-FTD.
- 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. PMID 20371462
- 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