The Wong Laboratory is in the Division of Neuropathology at the Johns Hopkins University School of Medicine. The overarching themes focus on the biology and pathobiology of an RNA splicing factor termed TDP-43 (TAR DNA/RNA binding protein 43kDa) that regulate the inclusion of cryptic exons, the loss of which underlies the pathogenic mechanism of several human age-related degenerative diseases, including Alzheimer’s Disease Related Dementia (ADRD), Amyotrophic Lateral Sclerosis (ALS), as well as Inclusion Body Myositis (IBM).
Ongoing projects include:
the development of in vitro and in vivo models of TDP-43 loss-of-function in the nervous system and skeletal muscle to reveal its biology in a cell- or organ-specific manner;
the development of mouse models that reflect disease-specific mimics of ADRD, including AD-TDP and FTLD-TDP subtypes and IBM;
testing of an AAV9 gene therapeutic strategy and the development of prognostic fluid biomarkers for these human diseases.
Below illustrates some of our recent works (click on each item to read more):
1. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD.(Science, 349(6248), 650-655, 2015)
2. Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration inanAlzheimer’s mouse model.
3. Cryptic exon incorporation occurs in Alzheimer’s brain lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43. (Acta Neuropathologica 133:923-931, 2017)
4. Splicing repression is a major function of TDP-43 in motor neurons. (Acta Neuropathologica July 22, 2019; doi.org/10.1007/s00401-019-02042-8).
5. Loss of TDP-43 function and rimmed vacuoles persist after T cell depletion in a xenograft model of sporadic inclusion body myositis. (Science Translational Medicine 14, eabi9196, January 19, 2022)