L. Guo, H.J. Kim, H. Wang, J. Monaghan, F. Freyermuth, J.C. Sung, K. O’Donovan, C.M. Fare, Z. Diaz, N. Singh, Z.C. Zhang, M. Coughlin, E.A. Sweeny, M.E. DeSantis, M.E. Jackrel, C.B. Rodell, J.A. Burdick, O.D. King, A.D. Gitler, C. Lagier-Tourenne, U.B. Pandey, Y.M. Chook, J.P. Taylor, and J. Shorter. Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains. Cell. 2018, 173(3):677-692.

We establish that nuclear-import receptors (NIRs) specifically chaperone and potently disaggregate wild-type and disease-linked RNA-binding Proteins (RBPs) bearing a Nuclear Localization Signal (NLS). Our results show that nuclear-localization sequences (NLSs) are disaggregation signals in the cytoplasm. NIRs rescue degeneration caused by disease-linked FUS and hnRNPA2 in vivo.

Zhang, Y-J., L. Guo, P.K. Gonzales, T.F. Gendron, Y. Wu, K. Jansen-West, A.D. O’Raw, S.R. Pickles, M. Prudencio, Y. Carlomagno, M.A. Gachechiladze, C. Ludwig, R. Tian, J. Chew, M. DeTure, W-L. Lin, J. Tong, L.M. Daughrity, M. Yue, Y. Song, J.W. Andersen, M. Castanedes-Casey, A. Kurti, A. Datta, G. Antognetti, A. McCampbell, R. Rademakers, B. Oskarsson, D.W. Dickson, M. Kampmann, M.E. Ward, J.D. Fryer, C.D. Link, J. Shorter, and L. Petrucelli. Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity. Science. 2019, 363.

By disrupting HP1α liquid phases, interacting with heterochromatin, and eliciting aberrant histone posttranslational modifications, poly(PR) adversely influences heterochromatin structure. Consequently, repetitive element expression is induced and doublestranded RNA accumulates, contributing to the neurodegeneration seen in patients with c9FTD/ALS.

J.R. Mann, A.M. Gleixner, J.C. Mauna, E. Gomes, M.R. DeChellis-Marks, P.G. Needham, K.E. Copley, B. Hurtle, B. Portz, N.J. Pyles, L. Guo, C.B. Calder, Z.P. Wills, U.B. Pandey, J.K. Kofler, J.L. Brodsky, A. Thathiah, J. Shorter, and C.J. Donnelly. RNA binding antagonizes neurotoxic phase transitions of TDP-43. Neuron. 2019, 102(2):321-338. 

RNA binding antagonizes aberrant liquid-liquid phase separation (LLPS) and aggregation of TDP-43. TDP-43 targeting oligonucleotides prevent aberrant LLPS and rescues neurotoxicity.

L. McGurk, E. Gomes, L. Guo, J. Shorter, and N.M. Bonini. Poly(ADP-ribose) engages the TDP-43 nuclear-localization sequence to regulate granulo-filamentous aggregation. Biochemistry. 2018.

We established that the N-terminal region of TDP-43 is critical for rapid granulo-filamentous aggregation. We showed that the biopolymer poly(ADP-ribose), or PAR, inhibits granulo-filamentous aggregation of TDP-43 by engaging PAR-binding motifs (PBMs) embedded in the TDP-43 nuclear-localization sequence.

L. Guo, K. B. Smith-Dupont and F. Gai. Diffusion as a probe of peptide-induced membrane domain formation. Biochemistry 2011, 50, 2291-2297.

We developed Fluorescence Correlation Spectroscopy (FCS) based single-molecule methods to investigate the aggregation mechanism of antimicrobial peptides (AMP) in the membrane environment. Our results indicate that AMP molecules prompt lipid domain formation in membranes, and are likely located at the boundary regions separating various domains and acting as mobile fences.