Publications
ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice
Schuster KH, Zalon AJ, DiFranco DM, Putka AF, Stec NR, Jarrah S, Naeem A, Haque Z, Guan Y, McLoughlin HS: Molecular Therapy. 2024; PMID: 38429929Similar to other paradigmatic neurodegenerative diseases, studies evaluating the pathogenic mechanism focus primarily on neuronal implications. Consequently, therapeutic interventions generated to target these deficiencies often overlook non-neuronal contributions to disease. Our lab recently reported that oligodendrocytes display some of the earliest and most progressive dysfunction in SCA3 mice. Evidence of disease-associated oligodendrocyte signatures has also been reported in other neurodegenerative diseases, including Alzheimer's disease, ALS, Parkinson's disease, and Huntington's disease. Here, we assess the effects of anti-ATXN3 antisense oligonucleotide (ASO) treatment on oligodendrocyte dysfunction in both premanifest and symptomatic SCA3 mouse models. We report a severe, but modifiable, deficit in oligodendrocyte maturation caused by the toxic gain-of-function of mutant ATXN3 early in SCA3 disease progression that is transcriptionally, biochemically, and functionally rescued with anti-ATXN3 ASO. Our results establish the necessity of considering non-neuronal targets in future neurodegenerative disease therapies.
ASO silencing reverses abnormal neurochemistry in spinocerebellar ataxia type 3 mice. McLoughlin HS, Gundry K, Rainwater O, Schuster KH, Wellik IG, Zalon AJ, Benneyworth MA, Eberly LE, Öz G. Annals of Neurology. 2023; PMID: 37243335.
This study reveals that YACQ84 SCA3 mice exhibit significant neurochemical abnormalities, indicative of neurodegeneration as well as glial contributions to disease. Treatment with anti-ATXN3 ASOs rescues select neurochemical abnormalities, demonstrating correlations between neurochemical rescue and reversal of the ataxic behavioral phenotype.
Blood neurofilament light chain levels are associated with disease progression in a transgenic SCA3 mouse model. Mengel D, Wellik IG, Schuster KH, Jarrah SI, Wacker M, Ashraf NS, Öz G, Synofzik M, Costa MC, McLoughlin HS. Disease Models and Mechanisms. 2023 PMID: 37664882
This study found that in the peripheral blood of SCA3 YACQ84 mice increased abundance of neuronal-specific NfL protein directly associated with disease progression, providing an accessible disease biofluid biomarker to interrogate in preclinical therapeutic studies.
Standards of fluid biomarker collection and pre-analytical processes in humans and mice: recommendations by the Ataxia Global Initiative Working Group on biomarkers. Santorelli FM, McLoughlin HS, Wolter JM, Galatolo D, Synofzik M, Mengel D, Opal P, on behalf of the AGI-W2-Biomarker study group. Cerebellum. 2023; PMID: 37243885.
This report outlines the work of the AGI fluid biomarker working group (WG) in creating standardized protocols for collecting and storing biomarkers in both human and preclinical mouse studies. The goal of this effort is to decrease variability in collection, resulting in more accurate downstream analysis and improved statistical power with the potential for reducing sample size. The focus of the group has been on defining and standardizing the collection and pre-analytical work-up of a minimal set of biological samples, specifically blood plasma and serum, while keeping in mind the need for cost-effective and resource-efficient harmonization of collection and storage methods.
Myelinating Glia: Potential Therapeutic Targets in Polyglutamine Spinocerebellar Ataxias. Putka AF, Mato JP, and McLoughlin HS. Cells. 2023; 12(4):601. PM36931268/PMC9953858.
In this special issue of Cells for "Emerging Therapies for Hereditary Ataxia", we review the contributions of central and peripheral myelinating glial to the pathomechanisms of polyglutamine spinocerebellar ataxias.
Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in Spinocerebellar Ataxia Type 3.
Schuster KH, Difranco DM, Putka AF, Mato JP, Jarrah SI, Stec, Sundararajan VO, & McLoughlin HS. Frontiers in Neuroscience. 2023; 17. https://doi.org/10.3389/fnins.2023.1118429Here, we describe the spatiotemporal progression of mature oligodendrocyte transcript dysregulation and cell count reduction in mouse models of SCA3.
Diverse Regional Mechanisms Drive Spinocerebellar Ataxia Type 1 Phenotypes. Putka AF and McLoughlin HS. Neuron. 2023; 111 (4) P447-449. PM36796325.
In this issue of Neuron, we previewed a pair of studies by Handler et al. 2023 and Coffin et al. 2023 that elucidate new insights into Spinocerebellar ataxia type 1 (SCA1) pathogenesis by genetically assessing mechanistic drivers of regional vulnerability and their relationships to SCA1-phenotypes.
Disease-associated oligodendrocyte signatures in neurodegenerative disease: the known and the unknown
Schuster KH and McLoughlin HS. Neural Regen Res 2023; 18(10):2192-2193. PM37056132In this perspective, we discussed the toolkit for studying oligodendrocytes in vivo and in vitro.
Pathogenic mechanisms underlying Spinocerebellar Ataxia Type 3 are altered in primary oligodendrocyte culture
Schuster KH, Putka AF, and McLoughlin HS Cells. 2022; 11(16):2615. PM36010688/PMC9406561.This image shows a graphical overview of the histological changes found in SCA3 and Atxn3-KO oligodendrocyte primary cell cultures relative to wildtype cultures.
Impaired oligodendrocyte maturation is an early feature in SCA3 disease pathogenesis.
Schuster KH, Zalon AJ, Zhang H, DiFranco DM, Stec NR, Haque Z, Blumenstein KG, Pierce AM, Guan Y, Paulson HL, McLoughlin HS: J Neurosci, 2022: 42 (8) 1604-1617. PM35042771/PMC8883861Despite advances in SCA3 disease understanding, much remains unknown about how the disease gene causes brain dysfunction ultimately leading to cell death. We completed a longitudinal transcriptomic analysis of vulnerable brain regions in SCA3 mice to define the earliest and most robust changes across disease progression. Through gene network analyses followed up with biochemical and histological studies in SCA3 mice, we provide evidence for severe dysfunction in oligodendrocyte maturation early in SCA3 pathogenesis. Our results advance understanding of SCA3 disease mechanisms, identify additional routes for therapeutic intervention, and may provide broader insight into polyglutamine diseases beyond SCA3.
This image shows a maturing oligodendrocyte cultured from a 7-day-old mouse brain. Mature oligodendrocyte marker, MBP is shown in red, immature oligodendrocyte marker Smoc1 is shown in green, and ATXN3 is shown in white. Nuclei are stained blue (DAPI). Deficits in oligodendrocyte maturation were recently discovered early in SCA3 pathogenesis. For more information, see the article by Schuster et al. 2022.
Antisense oligonucleotide therapy targeted against ATXN3 improves potassium channel-mediated Purkinje neuron dysfunction.
Bushart DD, Zalon AJ, Zhang H, Morrison LM, Guan YF, Paulson HL, Shakkottai VG, McLoughlin HS: The Cerebellum 2021; 20(1):41-53. PM32789747/PMC7930886.In early-stage SCA3 mice, we confirm a previously identified increase in excitability of cerebellar Purkinje neurons and associate this excitability with reduced transcripts of two voltage-gated potassium (KV) channels, Kcna6 and Kcnc3, as well as motor impairment. Intracerebroventricular delivery of antisense oligonucleotides (ASO) to reduce mutant ATXN3 restores normal excitability to SCA3 Purkinje neurons and rescues transcript levels of Kcna6 and Kcnc3. We concluded that the early rescue of both KV channel expression and neuronal excitability by ASO treatment suggests that cerebellar cortical dysfunction contributes meaningfully to motor dysfunction in SCA3.
Fig 1. Quantitative real-time PCR validation in 16-week-old vehicle- and ASO-5-treated mice of differentially regulated potassium channel genes, g Kcna6 and h Kcnc3.
Toward allele-specific targeting therapy and pharmacodynamic marker for Spinocerebellar Ataxia type 3.
Prudencio M, Garcia-Moreno H, Jansen-West KR, ...McLoughlin HS...Wszolek ZK, Giunti P, Petrucelli L: Science Translational Medicine 2020; 12(566):eabb7086. PM33087504/PMC7927160.Here, we helped develop an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias.
In vivo molecular signatures of cerebellar pathology in spinocerebellar ataxia type 3.
Costa MC, Radzwion M, McLoughlin HS, Ashraf NS, Fischer S, Shakkottai VG, Maciel P, Paulson HL, Öz G. Movement Disorders 2020; 35(10):1774-1786. PM32621646/PMC7572607.In this study, we sought to identify shared in vivo neurochemical signatures in two mouse models of SCA3 that reflect the human disease pathology and found N-acetylaspartate, myo-inositol, and total choline levels in the cerebellum are candidate biomarkers of neuroaxonal and oligodendrocyte pathology in SCA3, aspects of pathology that are reversible by RNAi therapy.
Pathogenesis of SCA3 and implications for other polyglutamine diseases.
McLoughlin HS, Moore LR, Paulson HL. Neurobiology of Disease. 2020; 134:104635. PM31669734/PMC6980715.In this review, we summarize current understanding of SCA3 disease mechanisms within the broader context of the broader polyQ disease field. We emphasize properties of the disease protein, ATXN3, and new discoveries regarding three potential pathogenic mechanisms: 1) altered protein homeostasis; 2) DNA damage and dysfunctional DNA repair; and 3) nonneuronal contributions to disease. We conclude with an overview of the therapeutic implications of recent mechanistic insights.
Synthetic high-density lipoprotein nanoparticles for the treatment of Niemann-Pick Diseases.
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. BMC Medicine. 2019; 17(1):200. PM31711490/PMC6849328.The study established that sHDL nanoparticles are a potential new therapeutic avenue for Niemann-Pick diseases. McLoughlin lab assisted with in vivo delivery experiments.
Antisense oligonucleotide therapy rescues aggresome formation in a novel Spinocerebellar Ataxia type 3 human embryonic stem cell line.
Moore LR, Keller L, Bushart DD, Delatorre R, Li D, McLoughlin HS, Costa MDC, Shakkottai VG, Smith GD, Paulson HL. Stem Cell Research. 2019; 39:101504. Epub. PM31374463/PMC6736695.This study characterized the first NIH-approved human embryonic stem cell (hESC) line derived from an embryo harboring the SCA3 mutation. The SCA3-hESC line offers a unique and highly relevant human disease model that holds strong potential to advance understanding of SCA3 disease mechanisms and facilitate the evaluation of candidate therapies for SCA3.
Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice.
McLoughlin HS, Moore LR, Chopra R, Komlo R, McKenzie M, Blumenstein KG, Zhao H, Kordasiewicz HB, Shakkottai VG, Paulson HL: Annal of Neurology 2018; 84(1): 64-77. PM29908063/PMC6119475.We investigated whether an antisense oligonucleotide (ASO) targeting the SCA3 disease gene, ATXN3, can prevent molecular, neuropathological, electrophysiological, and behavioral features of the disease in a mouse model of SCA3. This preclinical study established efficacy of ATXN3-targeted ASOs as a disease-modifying therapeutic strategy for SCA3. These results support further efforts to develop ASOs for human clinical trials in this polyglutamine disease.
Loss of the Spinocerebellar Ataxia type 3 disease protein ATXN3 alters transcription of multiple signal transduction pathways.
Zeng L, Zhang D, McLoughlin HS, Zalon AJ, Aravind L, Paulson HL: PLoS One 2018; 13 (9): e0204438. PM30231063/PMC6145529.In this study, we assessed the potential normal role of ATXN3 in regulating gene expression by comparing transcriptional profiles in WT versus Atxn3 null mouse embryonic fibroblasts. Together these results reveal a normal role for ATXN3 in transcriptional regulation of multiple signaling pathways of potential relevance to disease processes in SCA3.
Figure 1. Signal transduction pathways dysregulated by ATXN3 knockout in MEFs.
Evaluation of Antisense Oligonucleotides Targeting ATXN3 in SCA3 Mouse Models.
Moore LR, Rajpal G, Dillingham IT, Qutob M, Blumenstein KG, Gattis D, Hung G, Kordasiewicz HB, Paulson HL, McLoughlin HS: Molecular Therapy Nucleic Acids 2017; 7: 200-210. PM28624196/PMC5415970.In this manuscript, we reported that antisense oligonucleotides (ASOs) targeting full-length human ATXN3 could lead to a preventative therapy for Spinocerebellar ataxia type 3 (SCA3), as it was potent, well tolerated, and broadly distributed throughout the CNS.
Human-specific microRNA regulation of FOXO1: implications for microRNA recognition element evolution.
McLoughlin HS, Wan J, Spengler RM, Xing Y, Davidson BL: Human Molecular Genetics 2014; 23(10): 2593-603. PM24368418.Study testing the hypothesis that in transcription factor 3'UTRs, human-specific single nucleotide change(s) that create novel miRNA recognition elements (MREs) contribute to species-specific differences in transcription factor expression. From several potential human-specific TF MREs, one candidate, a member of the Forkhead Box O (FOXO) subclass in the Forkhead family known as Forkhead Box O1 (FOXO1; FKHR; NM_002015) was tested further. These results provide strong evidence for human-specific gain of TF MREs, a process that may underlie evolutionary differences between phylogenic groups.
Dicer is required for proliferation, viability, migration and differentiation in corticoneurogenesis.
McLoughlin HS, Fineberg SK, Ghosh LL, Tecedor L, Davidson BL: Neuroscience 2012; 223: 285-95. PM22898830/PMC3472421.This study assessed the impact of miRNAs on neural progenitor cell proliferation, apoptosis, migration, and differentiation in the developing mouse brain.
