The<\/span>\u00a0Christopher<\/span>\u00a0<\/span>Pearson Lab<\/span>\u00a0is dedicated to understanding repeat expansion diseases by investigating their underlying molecular mechanisms and exploring therapeutic strategies. Using a wide range of experimental models\u2014including\u00a0<\/span>patient<\/span><\/span>\u2011<\/span>derived<\/span>\u00a0cell lines, mouse models of disease, and\u00a0<\/span>post<\/span><\/span>\u2011<\/span>mortem<\/span> human tissues\u2014the lab integrates basic and translational research approaches. These efforts are organized around several key research themes that aim to elucidate disease pathogenesis and advance the development of effective treatments.<\/span><\/span><\/span><\/p>\n<\/div><\/div><\/div><\/div><\/div><\/path><\/svg><\/div><\/div><\/div><\/div>
Disease & Therapy<\/h2><\/div><\/div><\/div>A major focus of the Christopher Pearson Lab is developing disease\u2011modifying therapies for CAG repeat expansion disorders, with Huntington\u2019s disease (HD) as a central model. HD is caused by inherited CAG expansions in HTT that undergo further somatic expansion in vulnerable brain regions, accelerating disease onset and progression. Our work targets the DNA structures that drive pathological repeat expansion, leading to the discovery of the small molecule naphthyridine\u2011azaquinolone (NA), which selectively binds slipped CAG DNA intermediates and induces contraction of expanded repeats. NA promotes mutant\u2011allele\u2013specific repeat contraction through transcription\u2011 and MutS\u03b2\u2011dependent pathways, independently of DNA replication. In HD patient cells and mouse models, NA\u2011induced contractions reduce mutant huntingtin aggregation, rescue molecular and cellular disease hallmarks, improve motor and behavioral phenotypes, and attenuate neurodegeneration, supporting somatic repeat expansion as a tractable therapeutic target. Extending this strategy to related CAG repeat diseases, we have demonstrated repeat contraction\u2013mediated therapeutic benefit in models of dentatorubral\u2011pallidoluysian atrophy (DRPLA), and we investigate shared and distinct mechanisms of striatal vulnerability in spinocerebellar ataxia type 1 (SCA1). Together, these studies establish targeting somatic repeat instability as a promising and broadly applicable therapeutic approach for CAG repeat disorders.<\/span><\/p>\n<\/div><\/div><\/div>In addition to CAG repeat expansions, our efforts to target pathogenic repeat DNA structures extend to other disease\u2011causing repeat motifs, including the GGGGCC hexanucleotide repeat associated with C9orf72\u2011linked neurodegenerative disorders. These GGGGCC repeats form abnormal DNA and RNA secondary structures that contribute to repeat instability, transcriptional dysregulation, and cellular toxicity. We are actively screening and characterizing a series of small\u2011molecule ligands designed to selectively bind these repeat\u2011associated structures, with the goal of reducing repeat length and mitigating downstream pathogenic processes. Using cellular and disease\u2011relevant model systems, we are evaluating the ability of these ligands to modulate repeat dynamics, suppress toxic species, and establish proof\u2011of\u2011principle for repeat\u2011structure\u2013targeted therapeutic strategies beyond CAG expansion diseases.<\/span><\/p>\n<\/div><\/path><\/svg><\/div><\/div><\/div><\/div><\/div><\/div><\/div><\/div>
Disease & Mechanism<\/h2><\/div>The Christopher Pearson Lab investigates how pathogenic repeat expansions disrupt genome stability, cellular homeostasis, and tissue\u2011specific vulnerability across a spectrum of neurodegenerative and neuromuscular disorders. Central to this work is understanding how repeat sequence composition and higher\u2011order DNA and RNA structures drive somatic repeat instability, chromosomal damage, and downstream molecular pathology. By combining repeat biology, genome instability, and structure\u2011based approaches, we define disease mechanisms in disorders caused by GGGGCC, CTG, and complex interrupted repeats, revealing shared principles and disease\u2011specific modifiers that shape onset, progression, and clinical severity. These mechanistic insights provide a foundation for identifying structure\u2011specific therapeutic targets across diverse repeat expansion diseases.<\/span><\/p>\n<\/div><\/div><\/div><\/div><\/div>GGGGCC repeat<\/strong><\/h3><\/div><\/div><\/div>We focus on ALS linked to C9orf72 repeat expansions and explore how both DNA repeat biology and small molecule targeting contribute to disease mechanisms. We study small molecules that bind the pathogenic (GGGGCC)n repeat and investigate how C9orf72 expansions destabilize the hyper unstable 9p21 chromosomal locus. We show that C9orf72 expansions induce a large, folate sensitive chromosomal fragile site (FRA9A), encompassing an extensive gene rich region that includes immune genes and oncogenes. This fragility drives somatic repeat instability, chromosomal breakage, rearrangements, and micronuclei formation, providing endogenous sources of damaged and immunostimulatory DNA that activate cGAS STING\u2013linked interferon and DNA damage responses. These defects are transferable in vivo, accumulate with age, and are modulated by folate levels, establishing C9orf72 expansions as a direct source of chromosomal instability and immune dysregulation in ALS and related neurodegenerative and autoimmune disorders.<\/span><\/p>\n<\/div><\/div><\/div><\/div><\/div>CTG Repeat Expansion Disorders<\/strong><\/h3><\/div><\/div><\/div>This project investigates a disease <\/span>modifying<\/span> strategy for myotonic dystrophy type 1 (DM1) by directly targeting pathogenic CTG repeat expansions in the DMPK gene. Building on our discovery of the small molecule DNA ligand naphthyridine azaquinolone (NA), which induces repeat contractions in CAG expansion diseases, we assess whether structure specific binding of slipped CTG DNA can similarly reverse somatic CTG expansions. Using a validated DM1 mouse model, we will examine <\/span>whether c<\/span> a compound can <\/span>modulate<\/span> repeat instability, toxic RNA pathology, and DM1 relevant neuromuscular and CNS phenotypes.<\/span><\/p>\n<\/div><\/div><\/div><\/div><\/div>Repeat Instability and Structural Determinants in XDP and CANVAS<\/b><\/h3><\/div><\/div><\/div>The\u00a0<\/span>Christopher Pearson Lab<\/span>\u00a0also investigates repeat expansion mechanisms in X linked dystonia parkinsonism (XDP) and cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) to understand how repeat sequence composition and structure\u00a0<\/span>modify<\/span>\u00a0disease expression. In XDP, caused by a polymorphic SINE VNTR Alu (AGAGGG)n\u00a0<\/span>insertion in<\/span>\u00a0TAF1, we\u00a0<\/span>identified<\/span>\u00a0mosaic divergent repeat interruptions (<\/span>mDRILS<\/span>) that influence repeat stability, generational transmission, and age at onset, highlighting the role of somatic mosaicism in disease modification. In CANVAS, we\u00a0<\/span>demonstrated<\/span>\u00a0that only pathogenic RFC1 repeat motifs form unusual DNA and RNA structures, including G quadruplexes and triplexes, providing a molecular explanation for disease specificity. Together, these studies reveal how repeat interruptions, structure, and instability contribute to neurodegeneration and uncover structure specific targets for therapeutic intervention<\/span><\/span><\/p>\n<\/div><\/div><\/div><\/div><\/div>DNA Repair Proteins And Repeat Diseases<\/b><\/h3><\/div><\/div><\/div>Pathogenic DNA repeat expansions arise from aberrant processing of secondary DNA structures formed during replication, transcription, and repair, implicating DNA repair proteins as key modifiers of disease onset and progression. The\u00a0<\/span>Christopher Pearson Lab<\/span>\u00a0investigates how\u00a0<\/span>structure<\/span><\/span>\u2011<\/span>specific<\/span>\u00a0DNA repair factors recognize, process, or misprocess\u00a0<\/span>slipped<\/span><\/span>\u2011<\/span>DNA<\/span>\u00a0intermediates, thereby influencing somatic repeat instability in the brain. By dissecting the roles of\u00a0<\/span>single<\/span><\/span>\u2011<\/span>stranded<\/span>\u00a0DNA\u2013binding complexes and repair nucleases, we uncover how distinct DNA repair pathways can either protect against or promote repeat expansion,\u00a0<\/span>providing<\/span>\u00a0mechanistic insight into why disruption of genome maintenance disproportionately drives neurodegenerative repeat expansion diseases.<\/span><\/span><\/span><\/p>\n<\/div><\/div><\/div><\/div><\/div>Replication Protein A (RPA)<\/b><\/h3><\/div><\/div><\/div>Canonical replication protein A (RPA), composed of RPA1, RPA2, and RPA3, plays a protective role against pathogenic repeat expansion by stabilizing\u00a0<\/span>single<\/span><\/span>\u2011<\/span>stranded<\/span>\u00a0DNA intermediates that arise during\u00a0<\/span>slipped<\/span><\/span>\u2011<\/span>DNA<\/span>\u00a0formation. We found that RPA is upregulated in Huntington\u2019s disease (HD) and spinocerebellar ataxia type 1 (SCA1) patient brains and interacts with key modifiers of CAG repeat instability. Mechanistically, RPA enhances DNA duplex melting and promotes FAN1<\/span><\/span>\u2011<\/span>mediated excision and repair of slipped CAG structures, thereby suppressing somatic repeat expansions in human cells. In vivo, RPA overexpression in SCA1 mouse brains ablates CAG expansions, reduces ATXN1 aggregation and DNA damage, improves neuronal morphology, and rescues motor phenotypes,\u00a0<\/span>identifying<\/span>\u00a0RPA as a potent suppressor of\u00a0<\/span>disease<\/span><\/span>\u2011<\/span>driving<\/span>\u00a0repeat instability<\/span><\/span>.<\/span><\/span><\/span><\/p>\n<\/div><\/div><\/div><\/div><\/div>Alternative RPA (Alt\u2011RPA)<\/b><\/h3><\/div><\/div><\/div>Alternative RPA (<\/span>Alt<\/span><\/span>\u2011<\/span>RPA<\/span>), a\u00a0<\/span>primate<\/span><\/span>\u2011<\/span>specific<\/span>\u00a0<\/span>ssDNA<\/span><\/span>\u2011<\/span>binding<\/span>\u00a0complex consisting of RPA1, RPA3, and RPA4,\u00a0<\/span>exhibits<\/span>\u00a0a functional role distinct from\u00a0<\/span>canonical<\/span>\u00a0RPA in repeat expansion diseases.\u00a0<\/span>Alt<\/span><\/span>\u2011<\/span>RPA<\/span>\u00a0is similarly upregulated in HD and SCA1 brains but displays a divergent interactome that includes modifiers of repeat instability. In contrast to RPA,\u00a0<\/span>Alt<\/span><\/span>\u2011<\/span>RPA<\/span>\u00a0inhibits\u00a0<\/span>slipped<\/span><\/span>\u2011<\/span>DNA<\/span>\u00a0melting and suppresses FAN1<\/span><\/span>\u2011<\/span>mediated excision and repair of CAG\u00a0<\/span>slip<\/span><\/span>\u2011<\/span>outs<\/span>, thereby promoting repeat expansions in human cells. These opposing effects suggest an antagonistic interplay between RPA and\u00a0<\/span>Alt<\/span><\/span>\u2011<\/span>