Neurodegeneration is a poorly understood biomedical phenomenon and a major public health challenge in our increasingly aging society. Our recent work on an inherited form of Amyotrophic Lateral Sclerosis (ALS), which is caused by mutations in SOD1, has shown that protein misfolding may play a central role in the degeneration of motor neurons. It has become clear that further elucidation of the mechanisms of protein misfolding and quality control in neurons is a critical step toward understanding this form of ALS as well as many other neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s. Our goal is to describe at the molecular and cellular levels how specific neurons degenerate, how protein folding and misfolding operate in the cell, and how protective systems fail at disease stages.
To dissect the complex processes of neurodegeneration, we have established novel C. elegans and mouse models of ALS, which recapitulate major features of the disease, providing a unique avenue for our research. Using the C. elegans model and forward genetic screens, we are searching for key genes and pathways of neurodegeneration that are conserved in humans.
New discoveries of disease genes, such as TDP-43 and C9orf72, are accelerating our understanding of the molecular underpinnings of neurodegeneration. We use molecular and cellular, genetic, and biochemical approaches to elucidate how these genes function normally and how mutations lead to disease. The elucidation may ultimately lead to better treatments of these devastating diseases.
Ugolino J, Ji YJ, Conchina K, Chu J, Nirujogi RS, Pandey A, Brady NR, Hamacher-Brady A, Wang J. Loss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling. PLoS Genet. 2016 PMID: 27875531.
Periz G, Lu J, Zhang T, Kankel MW, Jablonski AM, Kalb R, McCampbell A, Wang J. Regulation of protein quality control by UBE4B and LSD1 through p53-mediated transcription. PLoS Biol. 2015 PMID: 25837623.
Zhang T, Baldie G, Periz G, Wang J. RNA-processing protein TDP-43 regulates FOXO-dependent protein quality control in stress response. PLoS Genet. 2014 PMID: 25329970.
Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, Maragakis NJ, Troncoso JC, Pandey A, Sattler R, Rothstein JD, Wang J. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. 2014 PMID: 24598541.
Zhang T, Hwang HY, Hao H, Talbot C Jr, Wang J. Caenorhabditis elegans RNA-processing protein TDP-1 regulates protein homeostasis and life span. J Biol Chem. 2012 PMID: 22232551. (Paper of the Week).