Dr. Hayley McLoughlin is an Assistant Professor in the University of Michigan Neurology Department, with a joint appointment in the Department of Human Genetics. She earned her Neuroscience doctoral degree in 2013 from the University of Iowa in Dr. Beverly Davidson's laboratory and completed a postdoctoral research fellowship under the guidance of Dr. Henry (Hank) Paulson at the University of Michigan. In her postdoc, she assessed the efficacy of antisense oligonucleotide therapy in mouse models of Spinocerebellar Ataxia type 3/Machado-Joseph disease (SCA3/MJD). In 2016, she was appointed to research faculty at the University of Michigan where her lab focuses on establishing pathogenic mechanisms and therapeutic interventions for neurodegenerative diseases with particular emphasis toward the polyglutamine disease, SCA3. SCA3 is a progressive, dominantly inherited neurodegenerative disease for which there currently is no treatment. Dr. McLoughlin has recently been appointed to the tenure-track at the University of Michigan, where she continues to lead SCA3 preclinical efforts toward antisense oligonucleotide (ASO) gene silencing and viral-mediated RNAi in collaboration with industry partners. In hopes of identifying additional routes for therapeutic intervention, discovery of novel disease biomarkers, and to provide broader insight into the polyglutamine diseases beyond SCA3, the McLoughlin lab also interrogates disease mechanisms using a variety of SCA3 cellular and animal disease models as well as human tissue and biofluid samples.
Areas of Interest
The McLoughlin lab uses a series of cell and mouse models coupled with analysis of human disease tissue to assess the following research focuses:
- Nonneuronal contributions to neurodegeneration:Our work investigates a significant gap in our understanding of SCA3 and other polyglutamine diseases: nonneuronal contributions to disease pathogenesis, specifically cells of the oligodendrocyte (OL) lineage. Studying their role in disease will define whether OLs need to be a target of emerging therapies, shed light on the importance of communication between neurons and glia in polyQ disease pathogenesis, and may identify robust OL biomarkers of disease progression that will aid in clinical trial endpoints.
- Therapeutic development for SCA3:
Because expression of the mutant ATXN3 protein is an early and necessary step in SCA3 disease pathogenesis, strategies to reduce expression of the disease gene or enhance clearance itself are high on the list of potential therapies. The lab is currently pursuing three preclinical research programs: a. ASO therapy; b. Viral-mediated RNAi therapy; c. Viral-mediated chaperone therapy. As a supplement to many of these programs, the lab is also assisting in the discovery and development of disease biomarkers.
Honors & Awards
2014 NIH T32 NRSA Post-doctoral Fellowship
2016 Neuroscience Day Best Research Fellow Poster, University of Michigan
2018 Young Investigator Best Talk Award at the UMHD9 meeting. Capri, Italy
2018 National Ataxia Foundation SCA Young Investigator Award
2021 Ad-Hoc NIH Neurological Sciences and Disorders (NSD-B) study section reviewer
2021 Ad-Hoc NIH Molecular, Cellular, and Developmental Neuroscience (MCDN-F) study section reviewer
2021 Ad-Hoc NIH Therapeutic Approaches to Genetic Diseases (TAG) study section reviewer
2022 Ad-Hoc NIH Neurological Sciences and Disorders (NSD-B) study section reviewer
06/2009-12/2013 PhD, Neuroscience, with honors, University of Iowa, Iowa City, IA
01/2014-04/2014 Postdoctoral Research Fellow, Internal Medicine, University of Iowa, Iowa City, IA
07/2014-10/2016 Postdoctoral Research Fellow, Neurology, University of Michigan, Ann Arbor, MI
10/2016-08/2019 Research Investigator in Neurology, University of Michigan, Ann Arbor, MI
09/2019-10/2021 Research Assistant Professor in Neurology, University of Michigan, Ann Arbor, Michigan
11/2021-present Assistant Professor in Neurology, University of Michigan, Ann Arbor, MI
12/2021-present Assistant Professor in Human Genetics, University of Michigan, Ann Arbor, MI
- Schuster KH, Zalon AJ, Zhang H, DiFranco DM, Stec NR, Haque Z, Blumenstein KG, Pierce AM, Barnes SL, Guan YF, Paulson HL, McLoughlin HS. Impaired oligodendrocyte maturation is an early feature in SCA3 disease pathogenesis. J Neurosci: 2022. (In Press) PM35042771.
- Ilnytska O, Lai K, Gorshkov K, Schultz ML, Tran BN, Jeziorek M, Kunkel TJ,Azaria RD, McLoughlin HS, Waghalter M, Xu Y, Schlame M, Altan-Bonnet N, Zheng W, Lieberman AP, Dobrowolski R, Storch J. Enrichment of NPC1-deficient cells with the lipid LBPA stimulates autophagy, improves lysosomal function, and reduces cholesterol storage. JBC. May 21;297(1):100813 (2021). PM34023384/PMC8294588.
- Bushart DD, Zalon AJ, Zhang H, Morrison LM, Guan YF, Paulson HL, Shakkottai VG, McLoughlin HS. Antisense oligonucleotide therapy targeted against ATXN3 improves potassium channel-mediated Purkinje neuron dysfunction. The Cerebellum Feb;20(1):41-53, (2021). PM32789747/PMC7930886.
- Prudencio M, Garcia-Moreno H, Jansen-West KR, AL-Shaikh R, Gendron TF, Heckman MG, Spiegel MR, Carlomagno Y, Daughrity LM, Song Y, Dunmore JA, Byron N, Oskarsson BE, Nicholson KA, Staff NP, Puschmann A, Lemos J, Januário C, LeDoux M, Friedman J, Shakkottai V, Paulson HL, McLoughlin HS, Konno T, Onodera O, Ikeuchi T, Tada M, John FD, Ataxia Work Group, Wszolek ZK, Giunti P, Leonard P. Towards allele-specific targeting therapy and pharmacodynamic biomarker for spinocerebellar ataxia 3. Science Translational Medicine 12(566):eabb7086,(2020).PM33087504/PMC7927160.
- Costa MC, Radzwion M, McLoughlin HS, Ashraf NS, Fischer S, Shakkottai VG, Maciel P, Paulson HL, Öz G. In vivo molecular signatures of cerebellar pathology in spinocerebellar ataxia type 3. Movement Disorders Oct;35(10):1774-1786, (2020). PM32621646/PMC7572607.
- McLoughlin HS, Moore LR, Paulson HL. Pathogenesis of SCA3 and implications for other polyglutamine diseases. Neurobiology of Disease 134:104635, (2020). PM31669734/PMC6980715.
- Schultz ML, Fawaz MV, Azaria RD, Hollon TC, Liu EA, Kunkel TJ, Halseth T, Krus KL, Ming R, Morin EE, McLoughlin HS, Bushart DD, Paulson HL, Shakkottai VG, Orringer DA, Schwendeman AS, Lieberman A. Synthetic high-density lipoprotein nanoparticles for the treatment of Niemann-Pick Diseases. BMC Medicine. 17(1):200, (2019). PM31711490/PMC6849328.
- Moore LR, Keller L, Bushart DD, Delatorre RG, Li D, McLoughlin HS, Costa MC, Shakkottai VG, Smith GD, Paulson HL: Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line. Stem Cell Res 39: 101504, (2019). PM31374463/PMC6736695.
- Zeng L, Zhang D, McLoughlin HS, Zalon AJ, Aravind L, Paulson HL: Loss of the Spinocerebellar Ataxia type 3 disease protein ATXN3 alters transcription of multiple signal transduction pathways. PLoS One 13 (9): e0204438, (2018). PM30231063/PMC6145529.
- McLoughlin HS, Moore LR, Chopra R, Komlo R, McKenzie M, Blumenstein KG, Zhao H, Kordasiewicz HB, Shakkottai VG, Paulson HL: Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice. Ann Neurol 84(1): 64-77, (2018). PM29908063/PMC6119475.
- Moore LR, Rajpal G, Dillingham IT, Qutob M, Blumenstein KG, Gattis D, Hung G, Kordasiewicz HB, Paulson HL, McLoughlin HS: Evaluation of Antisense Oligonucleotides Targeting ATXN3 in SCA3 Mouse Models. Mol Ther Nucleic Acids 7: 200-210, (2017). PM28624196/PMC5415970.
- McLoughlin HS, Wan J, Spengler RM, Xing Y, Davidson BL: Human-specific microRNA regulation of FOXO1: implications for microRNA recognition element evolution. Hum Mol Genet 23(10): 2593-603, (2014). PM24368418.
- McLoughlin HS, Fineberg SK, Ghosh LL, Tecedor L, Davidson BL: Dicer is required for proliferation, viability, migration and differentiation in corticoneurogenesis. Neuroscience 223: 285-95, (2012). PM22898830/PMC3472421.