Hannah Shorrock

Areas of Interest

• RNA-mediated mechanisms of disease pathogenesis in spinocerebellar ataxias
• Small molecule therapy development for CAG repeat expansion diseases
• Mechanism of non-canonical translational regulation in mammalian cells  

Research  

The Shorrock research group focuses on investigating RNA mediated mechanisms of disease pathogenesis and how these mechanisms can be targeted for therapeutic intervention in rare neurodegenerative diseases. In particular, the lab focuses on a group of spinocerebellar ataxia subtypes caused by inherited CAG repeat expansions to investigate the potential for shared therapeutics across this group of diseases. With a focus on repurposing and development of novel small molecule therapeutics, our research group uses a range of disease models from engineered screening cell lines to patient derived fibroblast cell lines, patient derived induced pluripotent stem cells and mouse models to assess therapeutic efficacy and mechanisms of action. 

Alongside our therapeutic focused work, we study the contribution of alternative splicing and RNA structure to disease processes and pathogenesis across multiple spinocerebellar ataxias and more broadly across neurodegenerative and neurological conditions. Understanding more about disease mechanisms and processes can help to identify novel cellular targets for development of therapeutic approaches and establish readouts for assessing therapeutic efficacy.  

Selected publications  

• NCBI Publications

Shorrock HK, Lennon CD, Aliyeva A, Davey EE, DeMeo CC, Pritchard CE, Planco L, Velez JM, Mascorro-Huamancaja A, Shin DS, Cleary JD, Berglund JA. Widespread alternative splicing dysregulation occurs presymptomatically in CAG expansion spinocerebellar ataxias. Brain. 2023 Sep 30; PubMed PMID: 37776516.

Davey EE, Légaré C, Planco L, Shaughnessy S, Lennon CD, Roussel MP, Shorrock HK, Hung M, Cleary JD, Duchesne E, Berglund JA. Individual transcriptomic response to strength training for patients with myotonic dystrophy type 1. JCI Insight. 2023 Jul 24;8(14) PubMed Central PMCID: PMC10443797.

Jenquin JR, O'Brien AP, Poukalov K, Lu Y, Frias JA, Shorrock HK, Richardson JI, Mazdiyasni H, Yang H, Huigens RW 3rd, Boykin D, Ranum LPW, Cleary JD, Wang ET, Berglund JA. Molecular characterization of myotonic dystrophy fibroblast cell lines for use in small molecule screening. iScience. 2022 May 20;25(5):104198. PubMed Central PMCID: PMC9035709.

Perez BA*, Shorrock HK*, Banez-Coronel M, Zu T, Romano LE, Laboissonniere LA, Reid T, Ikeda Y, Reddy K, Gomez CM, Bird T, Ashizawa T, Schut LJ, Brusco A, Berglund JA, Hasholt LF, Nielsen JE, Subramony SH, Ranum LP. CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity. EMBO Mol Med. 2021 Nov 8;13(11):e14095. PubMed Central PMCID: PMC8573593. *These authors contributed equally.

Ayhan F, Perez BA, Shorrock HK, Zu T, Banez-Coronel M, Reid T, Furuya H, Clark HB, Troncoso JC, Ross CA, Subramony SH, Ashizawa T, Wang ET, Yachnis AT, Ranum LP. SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F. EMBO J. 2018 Oct 1;37(19) PubMed Central PMCID: PMC6166133.

Shorrock HK, Gillingwater TH, Groen EJN. Molecular Mechanisms Underlying Sensory-Motor Circuit Dysfunction in SMA. Front Mol Neurosci. 2019;12:59. PubMed Central PMCID: PMC6409332.

Šoltić D, Shorrock HK, Allardyce H, Wilson EL, Holt I, Synowsky SA, Shirran SL, Parson SH, Gillingwater TH, Fuller HR. Lamin A/C dysregulation contributes to cardiac pathology in a mouse model of severe spinal muscular atrophy. Hum Mol Genet. 2019 Nov 1;28(21):3515-3527. PubMed Central PMCID: PMC6927462.

Shorrock HK, van der Hoorn D, Boyd PJ, Llavero Hurtado M, Lamont DJ, Wirth B, Sleigh JN, Schiavo G, Wishart TM, Groen EJN, Gillingwater TH. UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy. Brain. 2018 Oct 1;141(10):2878-2894. PubMed Central PMCID: PMC6158753.

Shorrock HK, Gillingwater TH, Groen EJN. Overview of Current Drugs and Molecules in Development for Spinal Muscular Atrophy Therapy. Drugs. 2018 Mar;78(3):293-305. PubMed Central PMCID: PMC5829132.

Boyd PJ, Tu WY, Shorrock HK, Groen EJN, Carter RN, Powis RA, Thomson SR, Thomson D, Graham LC, Motyl AAL, Wishart TM, Highley JR, Morton NM, Becker T, Becker CG, Heath PR, Gillingwater TH. Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy. PLoS Genet. 2017 Apr;13(4):e1006744. PubMed Central PMCID: PMC5417717.

Aliyeva A, Lennon CD, Cleary JD, Shorrock HK, Berglund JA. Dysregulation of alternative splicing is a transcriptomic feature of patient-derived fibroblasts from CAG repeat expansion spinocerebellar ataxias. Hum Mol Genet. 2024 Nov 26; PubMed PMID: 39589088.