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

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

The Canadian Open Neuroscience Platform-An open science framework for the neuroscience community.

Harding RJ, Bermudez P, Bernier A, Beauvais M, Bellec P, Hill S, Karakuzu A, Knoppers BM, Pavlidis P, Poline JB, Roskams J, Stikov N, Stone J, Strother S, Evans AC

PLoS Comput Biol. 2023-7-27 . 19(7):e1011230 .doi: 10.1371/journal.pcbi.1011230

PMID: 37498959

Delineation of functional subdomains of Huntingtin protein and their interaction with HAP40.

Alteen MG, Deme JC, Alvarez CP, Loppnau P, Hutchinson A, Seitova A, Chandrasekaran R, Silva Ramos E, Secker C, Alqazzaz M, Wanker EE, Lea SM, Arrowsmith CH, Harding RJ

Structure. 2023-6-20 . .doi: 10.1016/j.str.2023.06.002

PMID: 37390814

Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei.

MacDonald KM, Nicholson-Puthenveedu S, Tageldein MM, Khasnis S, Arrowsmith CH, Harding SM

Nat Commun. 2023-2-2 . 14(1):556 .doi: 10.1038/s41467-023-36195-8

PMID: 36732527

Detection of antibodies against the huntingtin protein in human plasma.

Denis HL, Alpaugh M, Alvarez CP, Fenyi A, Barker RA, Chouinard S, Arrowsmith CH, Melki R, Labib R, Harding RJ, Cicchetti F

Cell Mol Life Sci. 2023-1-18 . 80(2):45 .doi: 10.1007/s00018-023-04687-x

PMID: 36651994

2021

Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1.

Harding RJ, Deme JC, Hevler JF, Tamara S, Lemak A, Cantle JP, Szewczyk MM, Begeja N, Goss S, Zuo X, Loppnau P, Seitova A, Hutchinson A, Fan L, Truant R, Schapira M, Carroll JB, Heck AJR, Lea SM, Arrowsmith CH

Commun Biol. 2021-12-8 . 4(1):1374 .doi: 10.1038/s42003-021-02895-4

PMID: 34880419

Structure-Activity Relationship of USP5 Inhibitors.

Mann MK, Zepeda-Velázquez CA, González-Álvarez H, Dong A, Kiyota T, Aman AM, Loppnau P, Li Y, Wilson B, Arrowsmith CH, Al-Awar R, Harding RJ, Schapira M

J Med Chem. 2021-10-14 . .doi: 10.1021/acs.jmedchem.1c00889

PMID: 34648286