Rachel Harding

Rachel Harding

SGC Toronto

Harding

Biography

Dr. Harding is an Assistant Professor in the Faculty of Pharmacy, is a Principal Investigator at the Structural Genomics Consortium and is also cross-appointed to the Department of Pharmacology and Toxicology, all at the University of Toronto. Dr. Harding completed both her undergraduate (MBiochem) and graduate (DPhil) studies at the University of Oxford, the latter training in the lab of Dr. Susan Lea. Dr. Harding moved to the University of Toronto for her postdoctoral training in the lab of Dr. Cheryl Arrowsmith. Dr. Harding was awarded the prestigious Huntington’s Disease Society of America Berman-Topper Family Career Development Fellowship for her research on the structure-function of the Huntington’s disease protein, huntingtin, work that has continued into her independent research career. Her contributions to the field of Huntington’s were further recognised with her award of the 2024 Nancy Wexler Young Investigator Prize, an honour bestowed upon a researcher whose work reflects the highest calibre of excellence, diligence and creative thinking.

Research Areas

Dr. Harding's team uses structural biology, protein biochemistry and chemical biology to study the molecular mechanisms of pathology of repeat expansion disorders, with a primary focus on Huntington’s disease. Huntington’s is a devastating, incurable, genetic, neurodegenerative disease caused by a CAG-tract expansion in the Huntingtin gene. The group is concentrated on three key areas: 1) defining the structure-function relationship of the Huntington’s disease protein, huntingtin, and how this is altered by the disease-causing mutation; 2) molecular mechanisms of repeat expansion disorders like Huntington’s; and 3) development of chemical tools targeting understudied proteins and targets of interest for Huntington’s disease drug discovery.

2024

CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson's Disease Associated Protein.

Li F, Ackloo S, Arrowsmith CH, Ban F, Barden CJ, Beck H, Beránek J, Berenger F, Bolotokova A, Bret G, Breznik M, Carosati E, Chau I, Chen Y, Cherkasov A, Corte DD, Denzinger K, Dong A, Draga S, Dunn I, Edfeldt K, Edwards A, Eguida M, Eisenhuth P, Friedrich L, Fuerll A, Gardiner SS, Gentile F, Ghiabi P, Gibson E, Glavatskikh M, Gorgulla C, Guenther J, Gunnarsson A, Gusev F, Gutkin E, Halabelian L, Harding RJ, Hillisch A, Hoffer L, Hogner A, Houliston S, Irwin JJ, Isayev O, Ivanova A, Jacquemard C, Jarrett AJ, Jensen JH, Kireev D, Kleber J, Koby SB, Koes D, Kumar A, Kurnikova MG, Kutlushina A, Lessel U, Liessmann F, Liu S, Lu W, Meiler J, Mettu A, Minibaeva G, Moretti R, Morris CJ, Narangoda C, Noonan T, Obendorf L, Pach S, Pandit A, Perveen S, Poda G, Polishchuk P, Puls K, Pütter V, Rognan D, Roskams-Edris D, Schindler C, Sindt F, Spiwok V, Steinmann C, Stevens RL, Talagayev V, Tingey D, Vu O, Walters WP, Wang X, Wang Z, Wolber G, Wolf CA, Wortmann L, Zeng H, Zepeda CA, Zhang KYJ, Zhang J, Zheng S, Schapira M

J Chem Inf Model. 2024-11-5 . .doi: 10.1021/acs.jcim.4c01267

PMID: 39499532

Poly ADP-ribose signaling is dysregulated in Huntington disease.

Maiuri T, Bazan CB, Harding RJ, Begeja N, Kam TI, Byrne LM, Rodrigues FB, Warner MM, Neuman K, Mansoor M, Badiee M, Dasovich M, Wang K, Thompson LM, Leung AKL, Andres SN, Wild EJ, Dawson TM, Dawson VL, Arrowsmith CH, Truant R

Proc Natl Acad Sci U S A. 2024-9-27 . 121(40):e2318098121 .doi: 10.1073/pnas.2318098121

PMID: 39331414

A guide to selecting high-performing antibodies for Huntingtin (UniProt ID: P42858) for use in western blot, immunoprecipitation, and immunofluorescence.

Fanti R, Ayoubi R, Alende C, Fotouhi M, González Bolívar S, Chandrasekaran R, Southern K, Edwards AM, Harding RJ, Laflamme C

F1000Res. 2024-9-11 . 13:922 .doi: 10.12688/f1000research.153670.1

PMID: 39257448

Autoinhibition of ubiquitin-specific protease 8: insights into domain interactions and mechanisms of regulation.

Caba C, Black M, Liu Y, DaDalt AA, Mallare J, Fan L, Harding RJ, Wang Y, Vacratsis PO, Huang R, Zhuang Z, Tong Y

J Biol Chem. 2024-8-28 . 107727 .doi: 10.1016/j.jbc.2024.107727

PMID: 39214302

Huntingtin is an RNA binding protein and participates in NEAT1-mediated paraspeckles.

Yadav M, Harding RJ, Li T, Xu X, Gall-Duncan T, Khan M, Bardile CF, Sequiera GL, Duan S, Chandrasekaran R, Pan A, Bu J, Yamazaki T, Hirose T, Prinos P, Tippett L, Turner C, Curtis MA, Faull RLM, Pouladi MA, Pearson CE, He HH, Arrowsmith CH

Sci Adv. 2024-7-19 . 10(29):eado5264 .doi: 10.1126/sciadv.ado5264

PMID: 39028820

Subpocket Similarity-Based Hit Identification for Challenging Targets: Application to the WDR Domain of LRRK2.

Eguida M, Bret G, Sindt F, Li F, Chau I, Ackloo S, Arrowsmith C, Bolotokova A, Ghiabi P, Gibson E, Halabelian L, Houliston S, Harding RJ, Hutchinson A, Loppnau P, Perveen S, Seitova A, Zeng H, Schapira M, Rognan D

J Chem Inf Model. 2024-6-25 . .doi: 10.1021/acs.jcim.4c00601

PMID: 38916159

Big data and benchmarking initiatives to bridge the gap from AlphaFold to drug design.

Schapira M, Halabelian L, Arrowsmith CH, Harding RJ

Nat Chem Biol. 2024-3-8 . .doi: 10.1038/s41589-024-01570-z

PMID: 38459278

Small Molecule Screen Identifies Non-catalytic USP3 Chemical Handle.

Mann MK, Wolf E, Silva M, Kwak HA, Wilson B, Bolotokova A, Wilson DJ, Harding RJ, Schapira M

ACS Omega. 2024-1-9 . 9(1):917-924 .doi: 10.1021/acsomega.3c07070

PMID: 38222562

2023

Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability.

Gall-Duncan T, Luo J, Jurkovic CM, Fischer LA, Fujita K, Deshmukh AL, Harding RJ, Tran S, Mehkary M, Li V, Leib DE, Chen R, Tanaka H, Mason AG, Lévesque D, Khan M, Razzaghi M, Prasolava T, Lanni S, Sato N, Caron MC, Panigrahi GB, Wang P, Lau R, Castel AL, Masson JY, Tippett L, Turner C, Spies M, La Spada AR, Campos EI, Curtis MA, Boisvert FM, Faull RLM, Davidson BL, Nakamori M, Okazawa H, Wold MS, Pearson CE

Cell. 2023-10-5 . .doi: 10.1016/j.cell.2023.09.008

PMID: 37827155

Discovery and Characterization of a Chemical Probe Targeting the Zinc-Finger Ubiquitin-Binding Domain of HDAC6.

Harding RJ, Franzoni I, Mann MK, Szewczyk MM, Mirabi B, Ferreira de Freitas R, Owens DDG, Ackloo S, Scheremetjew A, Juarez-Ornelas KA, Sanichar R, Baker RJ, Dank C, Brown PJ, Barsyte-Lovejoy D, Santhakumar V, Schapira M, Lautens M, Arrowsmith CH

J Med Chem. 2023-7-27 . .doi: 10.1021/acs.jmedchem.3c00314

PMID: 37499118