About

Dr. Sofia B. Lizarraga is a molecular biologist originally from Peru who completed her PhD at Johns Hopkins University, where she studied the assembly of the mitotic spindle under the mentorship of Dr. Yixian Zheng. Her fascination with the cytoskeleton's role in neuronal development led her to pursue postdoctoral research at Harvard Medical School with Dr. Christopher A. Walsh. Continuing her focus on neurodevelopmental disorders, particularly autism, she worked as an investigator with Dr. Eric M. Morrow at Brown University. Dr. Lizarraga established her independent research group at the University of South Carolina, where she developed a research program centered on chromatin regulatory mechanisms in human brain development. In early 2023, she relocated her laboratory to Brown University, where she was promoted with tenure to Associate Professor of Molecular Biology, Cell Biology & Biochemistry in 2025. Her laboratory is based at the Center for Translational Neuroscience. Outside of her scientific pursuits, Dr. Lizarraga enjoys art, the ocean, and foreign films.

Research topics

• Biology
• Cell biology
• Neuroscience
• Genetics
• Biochemistry
• Chemistry
• Medicine

Selected publications

• Tyrosine and Phenylalanine Activate Neuronal <scp>DNA</scp> Repair but Exhibit Opposing Effects on Global Transcription and Adult Female Mice Are Resilient to <scp>TyrRS</scp>/<scp>YARS1</scp> Depletion

  IUBMB Life · 2025-06-01 · 3 citations

  articleOpen access

  Serum tyrosine and phenylalanine levels increase during aging and age-associated disorders. We previously showed that tyrosyl-tRNA synthetase (TyrRS/YARS1) is reduced in Alzheimer's Disease (AD) brains, and tyrosine and phenylalanine decrease TyrRS in neurons. Here, we found that tau is a negative regulator, whereas estrogen and leucine act as positive regulators of TyrRS. Young female mice exhibit increased TyrRS in the cortex compared to male mice. Notably, young Tau knockout male, but not female mice showed increased cortical TyrRS. Tau accumulation in middle-aged female mice did not decrease cortical TyrRS compared to males, suggesting that middle-aged females are resilient to tau-mediated TyrRS depletion. Tyrosine and phenylalanine treatment decreased tubulin tyrosination, activated DNA repair pathways, and protected against etoposide (ETO) and camptothecin (CPT)-induced toxicity, respectively, in neurons. While tyrosine facilitated topoisomerase 1 (TOP1) recruitment to chromatin and inhibited global transcription, in contrast, phenylalanine recruited topoisomerase 2 beta (TOP2β) to chromatin and stimulated global transcription. Furthermore, tyrosine decreased the presence of DNA fragments in a comet assay whereas phenylalanine increased them. Addition of cis-resveratrol (cis-RSV) protected against tyrosine-induced transcription inhibition by facilitating the recruitment of both TOP1 and TOP2β to chromatin and increasing tubulin tyrosination. Moreover, cis-RSV decreased both total and phosphorylated tau and protected neurons against amyloid beta (Aβ)-induced neurite degeneration and DNA damage. Gene expression profiling using human embryonic stem cell (hESC)-derived neurons demonstrated that cis-RSV is a broad-spectrum neuroprotective and anti-viral agent. In contrast, trans-RSV mimics phenylalanine-induced gene expression, including downregulation of long genes and induction of an AD-like gene expression signature. This work suggests that age and disease-associated increases in serum tyrosine and phenylalanine levels would activate neuronal DNA repair while inhibiting transcription and tubulin tyrosination. cis-RSV protects against their toxicity by restoring tubulin tyrosination, TOP1 and TOP2β-mediated transcription, and decreasing tau in primary neurons.

  PublisherDOI

• Mutations in ASH1L cause a neurodevelopmental disorder with sex differences in epilepsy and autism

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-23 · 1 citations

  preprintOpen access

  Summary To understand brain phenotypes associated with ASH1L, we performed both studies in mouse models and clinical phenotyping of human subjects. We found in mice that ASH1L mutations result in seizures, microcephaly, and also less complex dendritic morphology. When we analyzed human subjects based for epilepsy, intellectual disability, and ASD, we found sex differences in epilepsy and autism, with epilepsy predominantly in female and ASD in male subjects. To understand the cellular and molecular mechanisms of the sex-difference, we performed whole cell patch clamp electrophysiology in mice and found hyperexcitability in female compared with male hippocampal CA1 neurons. We report the identification of sex-specific transcriptomic signatures resulting from ASH1L haploinsufficiency. Differentially expressed genes in female mice showed distinct association with epileptic encephalopathy, postnatal microcephaly and autistic behaviors. Thus, the role of ASH1L in specific circuits may be sex-dependent leading to sexual dimorphic effects from disruption of this gene.

  PublisherOA PDFDOI

• Dynamic Regulation OF The Chromatin Environment By Ash1L Modulates Human Neuronal Structure And Function

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-02

  preprintOpen accessSenior authorCorresponding

  Precise regulation of the chromatin environment through post-translational histone modification modulates transcription and controls brain development. Not surprisingly, mutations in a large number of histone-modifying enzymes underlie complex brain disorders. In particular, the histone methyltransferase ASH1L modifies histone marks linked to transcriptional activation and has been implicated in multiple neuropsychiatric disorders. However, the mechanisms underlying the pathobiology of ASH1L-asociated disease remain underexplored. We generated human isogenic stem cells with a mutation in ASH1L's catalytic domain. We find that ASH1L dysfunction results in reduced neurite outgrowth, which correlates with alterations in the chromatin profile of activating and repressive histone marks, as well as the dysregulation of gene programs important for neuronal structure and function implicated in neuropsychiatric disease. We also identified a novel regulatory node implicating both the SP and Krüppel -like families of transcription factors and ASH1L relevant to human neuronal development. Finally, we rescue cellular defects linked to ASH1L dysfunction by leveraging two independent epigenetic mechanisms that promote transcriptional activation. In summary, we identified an ASH1L-driven epigenetic and transcriptional axis essential for human brain development and complex brain disorders that provide insights into future therapeutic strategies for ASH1L-related disorders.

  PublisherOA PDFDOI

• The intersection of inflammation and DNA damage as a novel axis underlying the pathogenesis of autism spectrum disorders

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-11

  preprintOpen accessSenior authorCorresponding

  Autism spectrum disorders (ASD) affects 1 in 36 children and is characterized by repetitive behaviors and difficulties in social interactions and social communication. The etiology of ASD is extremely heterogeneous, with a large number of ASD cases that are of unknown or complex etiology, which suggests the potential contribution of epigenetic risk factors. In particular, epidemiological and animal model studies suggest that inflammation during pregnancy could lead to an increased risk of ASD in the offspring. However, the molecular mechanisms that contribute to ASD pathogenesis in relation to maternal inflammation during pregnancy in humans are underexplored. Several pro-inflammatory cytokines have been associated with increased autistic-like behaviors in animal models of maternal immune activation, including IL-17A. Using a combination of ASD patient lymphocytes and stem cell-derived human neurons exposed to IL-17A we discovered a shared molecular signature that highlights a metabolic and translational node that could lead to altered neuronal excitability. Further, our work on human neurons brings forward the possibility that defects in the DNA damage response could be underlying the effect of IL-17A on human excitatory neurons, linking exacerbated unrepaired DNA damage to the pathogenicity of maternal inflammation in connection to ASD.

  PublisherOA PDFDOI

• Neuroimmune mechanisms in autism etiology - untangling a complex problem using human cellular models

  Oxford Open Neuroscience · 2024-01-01 · 12 citations

  articleOpen accessSenior author

  Autism spectrum disorder (ASD) affects 1 in 36 people and is more often diagnosed in males than in females. Core features of ASD are impaired social interactions, repetitive behaviors and deficits in verbal communication. ASD is a highly heterogeneous and heritable disorder, yet its underlying genetic causes account only for up to 80% of the cases. Hence, a subset of ASD cases could be influenced by environmental risk factors. Maternal immune activation (MIA) is a response to inflammation during pregnancy, which can lead to increased inflammatory signals to the fetus. Inflammatory signals can cross the placenta and blood brain barriers affecting fetal brain development. Epidemiological and animal studies suggest that MIA could contribute to ASD etiology. However, human mechanistic studies have been hindered by a lack of experimental systems that could replicate the impact of MIA during fetal development. Therefore, mechanisms altered by inflammation during human pre-natal brain development, and that could underlie ASD pathogenesis have been largely understudied. The advent of human cellular models with induced pluripotent stem cell (iPSC) and organoid technology is closing this gap in knowledge by providing both access to molecular manipulations and culturing capability of tissue that would be otherwise inaccessible. We present an overview of multiple levels of evidence from clinical, epidemiological, and cellular studies that provide a potential link between higher ASD risk and inflammation. More importantly, we discuss how stem cell-derived models may constitute an ideal experimental system to mechanistically interrogate the effect of inflammation during the early stages of brain development.

  PublisherOA PDFDOI

• The power of human stem cell-based systems in the study of neurodevelopmental disorders

  Current Opinion in Neurobiology · 2024-09-17 · 8 citations

  reviewOpen accessSenior authorCorresponding

  Neurodevelopmental disorders (NDDs) affect 15% of children and are usually associated with intellectual disability, seizures, and autistic behaviors, among other neurological presentations. Mutations in a wide spectrum of gene families alter key stages of human brain development, leading to defects in neural circuits or brain architecture. Studies in animal systems have provided important insights into the pathobiology of several NDDs. Human stem cell technologies provide a complementary system that allows functional manipulation of human brain cells during developmental stages that would otherwise be inaccessible during human fetal brain development. Therefore, stem cell-based models advance our understanding of human brain development by revealing human-specific mechanisms contributing to the broad pathogenesis of NDDs. We provide a comprehensive overview of the latest research on two and three-dimensional human stem cell-based models. First, we discuss convergent cellular and molecular phenotypes across different NDDs that have been revealed by human iPSC systems. Next, we examine the contribution of in vitro human neural systems to the development of promising therapeutic strategies. Finally, we explore the potential of stem cell systems to draw mechanistic insight for the study of sex dimorphism within NDDs.

  PublisherDOI

• Interferome perturbation of human brain organoids induces progenitor and neuronal dysfunction seen in multiple sclerosis and autism (P2-3.015)

  Neurology · 2023-04-25

  article

  <h3>Objective:</h3> To characterize the effect of activation of the interferome in human organoids toward understanding human cortical neuronal dysfunction. <h3>Background:</h3> The mechanisms by which maternal infection and neuroinflammation impact human brain development, function, and repair remain unclear. IFN-g is a proinflammatory cytokine found elevated in serum of pregnant mothers with children diagnosed with autism and in Th1 cells in the cerebrospinal fluid of multiple sclerosis patients. <h3>Design/Methods:</h3> Nearly three hundred human cerebral organoids derived from iPSCs were used across all analyses. Organoids were continually exposed to IFN-g and compared to controls for up to 80 days in culture. 10X single-cell transcriptomics was performed at three timepoints, along with immunolabeling and pulse EdU experiments. Bioinformatic and Markov Chain analyses were used to determine the molecular, cellular, and systems level effects of IFN-g. <h3>Results:</h3> IFN-g exposure at low concentration restricts organoid growth across timepoints, diminishes the pool of cycling radial glia progenitors, and disrupts ventricular adherens cytoarchitecture. We find no evidence of cell cycle arrest or apoptosis, but rather an induction of premature neuronal differentiation and acceleration of neuronal maturation, that stems from cell-type-specific transcriptional rewiring by IFN-g, inducing expression of inflammatory and neurogenic genes that persists in all cell lineages. Markov chain modeling demonstrates that IFN-g targets differentiation lineages in a parallel pan-neuronal fashion. Finally, we find that cell-type-specific gene dysregulation induced by IFN-g overlaps with patient derived organoids from genetically linked autism spectrum disorder, and neuronal intrinsic dysregulation observed in cortical neurons in progressive multiple sclerosis. <h3>Conclusions:</h3> Our results show the feasibility of using a human brain organoid to model the effects of neuroinflammation on human brain development and function. This approach reveals a novel inflammatory mechanistic link with autism and identifies a critical network of neuronal identity and synaptic genes perturbed in multiple sclerosis recapitulated in a preclinical model. <b>Disclosure:</b> Ethan Hollingsworth has nothing to disclose. Mr. Julian has nothing to disclose. Fumihiro Watanabe has nothing to disclose. Mr. Reutershan has nothing to disclose. Miss Julian has nothing to disclose. Ms. Martorell Serra has nothing to disclose. Sofia Lizarraga has nothing to disclose. Dr. Hester has nothing to disclose. Dr. Imitola has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis . The institution of Dr. Imitola has received research support from biogen. Dr. Imitola has a non-compensated relationship as a Board Member with National MS Society that is relevant to AAN interests or activities. Dr. Imitola has a non-compensated relationship as a Committee Member with International Society for Stem Cell Research that is relevant to AAN interests or activities.

  PublisherDOI

• The Warburg micro syndrome protein RAB3GAP1 modulates neuronal morphogenesis and interacts with axon elongation end ER-Golgi trafficking factors

  Neurobiology of Disease · 2023-06-28 · 1 citations

  articleOpen accessSenior authorCorresponding

  RAB3GAP1 is GTPase activating protein localized to the ER and Golgi compartments. In humans, mutations in RAB3GAP1 are the most common cause of Warburg Micro syndrome, a neurodevelopmental disorder associated with intellectual disability, microcephaly, and agenesis of the corpus callosum. We found that downregulation of RAB3GAP1 leads to a reduction in neurite outgrowth and complexity in human stem cell derived neurons. To further define the cellular function of RAB3GAP1, we sought to identify novel interacting proteins. We used a combination of mass spectrometry, co-immunoprecipitation and colocalization analysis and identified two novel interactors of RAB3GAP1: the axon elongation factor Dedicator of cytokinesis 7 (DOCK7) and the TATA modulatory factor 1 (TMF1) a modulator of Endoplasmic Reticulum (ER) to Golgi trafficking. To define the relationship between RAB3GAP1 and its two novel interactors, we analyzed their localization to different subcellular compartments in neuronal and non-neuronal cells with loss of RAB3GAP1. We find that RAB3GAP1 is important for the sub-cellular localization of TMF1 and DOCK7 across different compartments of the Golgi and endoplasmic reticulum. In addition, we find that loss of function mutations in RAB3GAP1 lead to dysregulation of pathways that are activated in response to the cellular stress like ATF6, MAPK, and PI3-AKT signaling. In summary, our findings suggest a novel role for RAB3GAP1 in neurite outgrowth that could encompass the regulation of proteins that control axon elongation, ER-Golgi trafficking, as well as pathways implicated in response to cellular stress.

  PublisherDOI

• The role of histone methyltransferases in neurocognitive disorders associated with brain size abnormalities

  Frontiers in Neuroscience · 2023-02-10 · 19 citations

  reviewOpen accessSenior authorCorresponding

  Brain size is controlled by several factors during neuronal development, including neural progenitor proliferation, neuronal arborization, gliogenesis, cell death, and synaptogenesis. Multiple neurodevelopmental disorders have co-morbid brain size abnormalities, such as microcephaly and macrocephaly. Mutations in histone methyltransferases that modify histone H3 on Lysine 36 and Lysine 4 (H3K36 and H3K4) have been identified in neurodevelopmental disorders involving both microcephaly and macrocephaly. H3K36 and H3K4 methylation are both associated with transcriptional activation and are proposed to sterically hinder the repressive activity of the Polycomb Repressor Complex 2 (PRC2). During neuronal development, tri-methylation of H3K27 (H3K27me3) by PRC2 leads to genome wide transcriptional repression of genes that regulate cell fate transitions and neuronal arborization. Here we provide a review of neurodevelopmental processes and disorders associated with H3K36 and H3K4 histone methyltransferases, with emphasis on processes that contribute to brain size abnormalities. Additionally, we discuss how the counteracting activities of H3K36 and H3K4 modifying enzymes vs. PRC2 could contribute to brain size abnormalities which is an underexplored mechanism in relation to brain size control.

  PublisherOA PDFDOI

• Dysregulation of the chromatin environment leads to differential alternative splicing as a mechanism of disease in a human model of autism spectrum disorder

  Human Molecular Genetics · 2023-01-09 · 15 citations

  articleOpen accessSenior authorCorresponding

  Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants in ASD. Disruption of the chromatin environment leads to widespread dysregulation of gene expression, which is traditionally thought of as a mechanism of disease pathogenesis associated with ASD. Alternatively, alterations in chromatin dynamics could also lead to dysregulation of alternative splicing, which is understudied as a mechanism of ASD pathogenesis. The anticonvulsant valproic acid (VPA) is a well-known environmental risk factor for ASD that acts as a class I histone deacetylase inhibitor. However, the precise molecular mechanisms underlying defects in human neuronal development associated with exposure to VPA are understudied. To dissect how VPA exposure and subsequent chromatin hyperacetylation influence molecular signatures involved in ASD pathogenesis, we conducted RNA sequencing (RNA-seq) in human cortical neurons that were treated with VPA. We observed that differentially expressed genes (DEGs) were enriched for mRNA splicing, mRNA processing, histone modification and metabolism related gene sets. Furthermore, we observed widespread increases in the number and the type of alternative splicing events. Analysis of differential transcript usage (DTU) showed that exposure to VPA induces extensive alterations in transcript isoform usage across neurodevelopmentally important genes. Finally, we find that DEGs and genes that display DTU overlap with known ASD-risk genes. Altogether, these findings suggest that, in addition to differential gene expression, changes in alternative splicing correlated with alterations in the chromatin environment could act as an additional mechanism of disease in ASD.

  PublisherOA PDFDOI

Recent grants

• Dietary Supplements and Inflammation Phase-2: Isoxanthohumol as a treatment for estrogen-deficient-induced visceral hyperalgesia.

  NIH · $37.0M · 2012–2025

Frequent coauthors

• Eric M. Morrow

  Bradley Hospital

  52 shared

• Andrew Wilde

  Canada Research Chairs

  39 shared

• Christiane Wiese

  33 shared

• Yixian Zheng

  Carnegie Institution for Science

  29 shared

• M Schmidt

  Brown University

  27 shared

• Ece D. Gamsiz Uzun

  John Brown University

  20 shared

• Lijun Zhang

  Beijing Anzhen Hospital

  20 shared

• Christopher A. Walsh

  Boston Children's Hospital

  20 shared

Labs

• Lizarraga LaboratoryPI

  Focus on the role of the cytoskeleton in neuronal development and neurodevelopmental disorders, with a focus on autism.

Education

• Ph.D.

  John Hopkins University

  2003

• B.S.

  University of Connecticut

  1996