My lab explores two related areas of research in neurodegenerative diseases 1) defining the molecular triggers and modulators of amyloidogenic protein aggregation and 2) mapping the protective functions of the chaperone in neurons. Our studies take advantage of high-throughput biochemical and cellular genetic screens to systematically determine the key factors we can exploit to develop new therapeutic and preventive strategies.
To maintain a healthy state, cells must constantly survey and regulate the quality of its proteins in a process called proteostasis. An integral component of the proteostasis system is a large group of proteins classified as molecular chaperones. Molecular chaperones recognize a myriad of misfolded substrates in cells and promote their proper folding or degradation via the formation of highly interconnected and adaptable networks consisting of other chaperones and the many facets of the proteostasis system.
The question of how molecular chaperones can effectively regulate the folding of hundreds of different proteins under a variety of challenging conditions including cellular stresses and disease states is of incredible interest to us. Moreover, we are dedicated to understanding how this robust molecular chaperone network ultimately fails in protein misfolding diseases such as Alzheimer’s Disease and Huntington’s Disease.
Our research is aimed at exposing the wiring of the molecular chaperone network in cells. We will use a blend of biochemical, cell biology and genetic approaches to profile and manipulate chaperone connections and functions. From this work, we hope to identify both the strengths and weaknesses in the molecular chaperone network and use these insights to better understand the cellular pathways that lead to disease.
Mok SA, Condello C, Freilich R, Gillies A, Arhar T, Oroz J, Kadavath H, Julien O, Assimon VA, Rauch JN, Dunyak BM, Lee J, Tsai FTF, Wilson MR, Zweckstetter M, Dickey CA, Gestwicki JE. Mapping interactions with the chaperone network reveals factors that protect against tau aggregation. Nat Struct Mol Biol. 2018 May;25(5):384-393. doi: 10.1038/s41594-018-0057-1. Epub 2018 Apr 30. PubMed PMID: 29728653; PubMed Central PMCID: PMC5942583.
Min SW, Sohn PD, Li Y, Devidze N, Johnson JR, Krogan NJ, Masliah E, Mok SA, Gestwicki JE, Gan L. SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy. J Neurosci. 2018 Apr 11;38(15):3680-3688. doi: 10.1523/JNEUROSCI.2369-17.2018. Epub 2018 Mar 14. PubMed PMID: 29540553; PubMed Central PMCID: PMC5895994.
Young ZT, Mok SA, Gestwicki JE. Therapeutic Strategies for Restoring Tau Homeostasis. Cold Spring Harb Perspect Med. 2018 Jan 2;8(1). pii: a024612. doi: 10.1101/cshperspect.a024612. Review. PubMed PMID: 28159830; PubMed Central PMCID: PMC5540800.
Rauch JN, Tse E, Freilich R, Mok SA, Makley LN, Southworth DR, Gestwicki JE. BAG3 Is a Modular, Scaffolding Protein that physically Links Heat Shock Protein 70 (Hsp70) to the Small Heat Shock Proteins. J Mol Biol. 2017 Jan 6;429(1):128-141. doi: 10.1016/j.jmb.2016.11.013. Epub 2016 Nov 21. PubMed PMID: 27884606; PubMed Central PMCID: PMC5186407.
Chen MZ, Mok SA, Ormsby AR, Muchowski PJ, Hatters DM. N-Terminal Fragments of Huntingtin Longer than Residue 170 form Visible Aggregates Independently to Polyglutamine Expansion. J Huntingtons Dis. 2017;6(1):79-91. doi: 10.3233/JHD-160207. PubMed PMID: 28339398.
Min SW, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, Shirakawa K, Minami SS, Defensor E, Mok SA, Sohn PD, Schilling B, Cong X, Ellerby L, Gibson BW, Johnson J, Krogan N, Shamloo M, Gestwicki J, Masliah E, Verdin E, Gan L. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015 Oct;21(10):1154-62. doi: 10.1038/nm.3951. Epub 2015 Sep 21. PubMed PMID: 26390242; PubMed Central PMCID: PMC4598295.
Walter GM, Raveh A, Mok SA, McQuade TJ, Arevang CJ, Schultz PJ, Smith MC, Asare S, Cruz PG, Wisen S, Matainaho T, Sherman DH, Gestwicki JE. High-throughput screen of natural product extracts in a yeast model of polyglutamine proteotoxicity.Chem Biol Drug Des. 2014 Apr;83(4):440-9. doi: 10.1111/cbdd.12259. PubMed PMID: 24636344; PubMed Central PMCID: PMC4068144.
Mok SA, Lund K, Lapointe P, Campenot RB. A HaloTag® method for assessing the retrograde axonal transport of the p75 neurotrophin receptor and other proteins in compartmented cultures of rat sympathetic neurons. J Neurosci Methods. 2013 Mar 30;214(1):91-104. doi: 10.1016/j.jneumeth.2013.01.006. Epub 2013 Jan 21. PubMed PMID: 23348044.
Mok SA, Lund K, Campenot RB. A retrograde apoptotic signal originating in NGF-deprived distal axons of rat sympathetic neurons in compartmented cultures.Cell Res. 2009 May;19(5):546-60. doi: 10.1038/cr.2009.11. PubMed PMID: 19188931.
Campenot RB, Lund K, Mok SA. Production of compartmented cultures of rat sympathetic neurons. Nat Protoc. 2009;4(12):1869-87. doi: 10.1038/nprot.2009.210. PubMed PMID: 20010935.
Mok SA, Campenot RB. A nerve growth factor-induced retrograde survival signal mediated by mechanisms downstream of TrkA.Neuropharmacology. 2007 Feb;52(2):270-8. Epub 2006 Sep 1. PubMed PMID: 16949623.