About

Dr. Alysson R. Muotri is a professor in the Departments of Pediatrics and Cellular & Molecular Medicine at the University of California, San Diego. His research focuses on understanding what makes humans uniquely human by studying the brain from evolutionary and developmental perspectives. Dr. Muotri's work involves differentiating stem cells to create "brain organoids" in the laboratory, which serve as models to study the molecular and cellular mechanisms underlying complex neurological disorders such as autism. This approach also facilitates the identification and testing of novel therapeutic strategies, potentially accelerating the transition of new drugs into clinical trials. His research highlights the evolutionary tradeoffs of the modern human brain, which, while granting advanced cognitive abilities, also increases susceptibility to neurological diseases.

Research topics

• Computer Science
• Biology
• Neuroscience
• Genetics
• Computational biology
• Cancer research
• Immunology
• Zoology
• Evolutionary biology
• Psychology
• Cognitive science
• Cell biology
• Virology
• Human–computer interaction

Selected publications

• SETD5 dysfunction in human astrocytes drives IL-6-mediated neuronal impairments via the JAK/STAT signaling pathway

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-07 · 1 citations

  articleOpen accessSenior author

  Abstract Intellectual disability (ID) and autism spectrum disorder (ASD) are neurodevelopmental conditions marked by lifelong impairments in cognitive, motor, and social functions. Hundreds of genetic variants have been linked to these disorders, including mutations in chromatin regulators such as the SET-domain-containing protein 5 ( SETD5 ) gene. Most studies linking SETD5 loss-of-function to ASD/ID have focused primarily on neurons. However, while SETD5 is highly expressed in astrocytes, its role in glia cells remains poorly understood. Here, we examine how dysfunction of SETD5 in human-induced pluripotent stem cell (hiPSC)-derived astrocytes affects neuronal physiology. We show that SETD5-deficient astrocytes have increased levels of extracellular reactive oxygen species (ROS), glutamate, and interleukins-6 and 8 (IL-6 and (IL-8). Elevated astrocytic IL-6 exerts a non-cell autonomous harmful effect on healthy neurons. Using SETD5-deficient astrocytes as a screening platform, we identify the JAK/STAT pathway as an upstream regulator of abnormal IL-6 accumulation associated with SETD5 dysfunction. Accordingly, pharmacological inhibition of JAK-STAT signaling restores extracellular IL-6 to basal levels and partially rescues astrocyte morphology and neuronal deficits. Collectively, these findings highlight the JAK/STAT pathway as a key regulator of SETD5-mediated astrocytic function and suggest its potential as a therapeutic target for astrocytic-driven neuronal impairments in ASD and ID.

  PublisherOA PDFDOI

• Author Reply to Peer Reviews of Transcriptional perturbation of LINE-1 elements reveals their cis-regulatory potential

  2026-03-11

  peer-review
  PublisherDOI

• Human milk oligosaccharides promote synaptogenesis and neurite outgrowth in human cortical organoids

  Biochemistry and Biophysics Reports · 2026-02-28

  articleOpen accessSenior authorCorresponding

  The first 1000 days of a child's life represent a critical window for brain development, during which nutrition exerts profound effects on the trajectories of neurodevelopment. Human Milk Oligosaccharides (HMOs), a major component of human milk, are largely indigestible by infants and are known to influence immunity, microbiome composition, and gut-brain signaling, but their direct role in neurodevelopment remains poorly understood. Here, we investigated the impact of HMOs on human cortical organoids, a physiologically relevant in vitro model of early brain development. We found that HMO treatment significantly enhanced neurite outgrowth and synaptogenesis in a dose-dependent manner. Global proteomic profiling further demonstrated the upregulation of proteins associated with neuronal differentiation, synaptic maturation, and cytoskeletal remodeling. Our findings suggest that HMOs can influence neurodevelopmental processes and highlight a potential role for maternal milk components in early brain development. • Human milk oligosaccharides (HMOs) modulate synaptic density in human cortical organoids. • HMOs influence neural connectivity during early development. • Genetic background shapes HMO-mediated effects. • HMOs upregulate RNA splicing pathways in cortical organoids.

  PublisherDOI

• Connexin-43 Restoration Alleviates Desmosomal Arrhythmogenic Cardiomyopathy

  Circulation Heart Failure · 2026-01-26 · 1 citations

  articleOpen access

  BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is a fatal genetic heart disease primarily caused by mutations in desmosomal genes, leading to impaired cell-cell adhesion, ventricular arrhythmias, and progressive heart failure. Although gene therapy for specific ACM populations shows promise, it remains unclear whether mutation-agnostic pathways dysregulated across desmosomal mutations could be exploited for therapeutic intervention in this genetically broad and severe population. The reduction in expression of the ventricular gap junction protein Cx43 (connexin-43) is a common molecular alteration underlying desmosomal junctional deficits and arrhythmias, suggesting a potential common underlying mechanism and a therapeutic target for ACM. We hypothesized that restoration of Cx43 expression could be a mutation-agnostic intervention for ACM. METHODS: We exploited adeno-associated-viral-mediated gene therapy to restore the gap junction protein, Cx43, in genetic mouse models and human stem cell models of ACM, harboring loss or mutations in desmosomal genes, including Dsp (desmoplakin), PKP2 (plakophilin-2), and DSG2 (desmoglein-2). RESULTS: Administration of AAV-Cx43 (adeno-associated-viral-mediated connexin-43) gene therapy alleviated the severe biventricular dilatation, contractile dysfunction, and arrhythmias, while prolonging lifespan in 2 severe desmosomal ACM mouse models, either harboring Dsp loss and a prevalent human PKP2 mutation. Viral-mediated restoration of Cx43 could also alleviate physiological deficits in ACM human induced pluripotent stem cell-derived cardiomyocytes harboring PKP2 and DSG2 mutations. Mechanistically, Cx43 targets desmosomal protein expression and relocalization to the cell junction to support their mechanical stabilization and coupling. CONCLUSIONS: By using mouse and human models of desmosomal ACM harboring different mutational backgrounds, we show the sufficiency of Cx43 gene therapy and its restoration to modify and alleviate ACM deficits. These data suggest that noncanonical functions of Cx43, including mechanical modulation and reassembly of the desmosome, are a therapeutic target with the potential to treat diverse ACM populations.

  PublisherOA PDFDOI

• Human ancestors were exposed to lead millions of years ago, and it shaped our evolution

  2025-10-15

  preprint
  PublisherDOI

• A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

  UNC Libraries · 2025-04-22

  articleOpen access
  PublisherDOI

• Interregional human assembloids recapitulate fetal brain morphologies and enhance neuronal complexity

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-25

  preprintOpen access

  Neuronal morphology governs how neurons connect, integrate, and process information, offering critical insights into the functional architecture of the brain. Characterizing the three-dimensional (3D) morphology of individual neurons is key not only for mapping circuit connectivity but also for understanding the cellular diversity that emerges during development. Neural organoids are valuable models of human brain development and disease, yet their morphological complexity remains poorly characterized despite advances in single-cell transcriptomics. Here, we use 3D confocal imaging and manual reconstruction of 735 neurons to analyze forebrain (dorsal and ventral) and thalamic (dorsal and ventral) organoids, as well as forebrain, thalamic, and corticothalamic assembloids. We find that organoids and assembloids exhibit distinct morphologies resembling fetal brain neurons, including immature pyramidal-like, double-bouquet, and bushy-like neurons. Interregional assembloids show greater neuronal morphological complexity than individual organoids, with more extensive dendritic branching, longer projections, and diverse soma shapes. Corticothalamic assembloids further display features of emerging connectivity. We observe dendritic spines with excitatory and inhibitory profiles and varicosities, indicative of maturing synaptic architecture. Together, our work makes an initial effort in describing the diversity of neuronal morphology in human neural organoids and assembloids. It further establishes structural phenotyping as a critical dimension for validating human neural models and underscores their value for modeling morphofunctional disorders.

  PublisherOA PDFDOI

• Nanobioreactor detection of space-associated hematopoietic stem and progenitor cell aging

  Cell stem cell · 2025-09-01 · 11 citations

  articleOpen access
  PublisherOA PDFDOI

• Dormant viral pathways underlie space-induced neural senescence

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-04 · 2 citations

  preprintSenior authorCorresponding

  SUMMARY Long-duration spaceflight is associated with neurological symptoms in astronauts, yet the underlying molecular mechanisms remain unclear. Using human brain organoids cultured aboard the International Space Station, we analyzed three independent spaceflights to demonstrate that exposure to the space environment triggers Space-Induced Neural Senescence (SINS), characterized by chromatin remodeling, mitochondrial dysfunction, and activation of viral-like transcriptional programs in the absence of infection. Multi-omics analyses identified upregulation of endogenous LINE-1 (L1) retroelements, whose activity was markedly enhanced in organoids lacking MECP2, a known L1 repressor implicated in Rett syndrome. The resulting accumulation of cytoplasmic L1 DNA elicited an IL-6-mediated inflammatory and neurotoxic response, which was reversed by reverse transcriptase inhibitors (RTi) such as lamivudine or stavudine. Parallel preclinical experiments in Mecp2 -deficient mice confirmed that RTi treatment restored neuronal morphology, synaptogenesis, function, cognition, and survival. These findings reveal that the space environment reactivates dormant genomic retroelements, providing an unexpected mechanistic insight into astronaut neurobiology and identifying a potential therapeutic strategy for both space-induced and terrestrial neurological conditions. Our pioneering study demonstrates the value of space-enabling research in accelerating drug discovery and disease treatment on Earth.

  PublisherDOI

• A modular CRISPRa system for molecular therapy of <i>FOXG1</i> syndrome

  NAR Molecular Medicine · 2025-04-17 · 1 citations

  articleOpen access

  Abstract To date, there is an unmet need for novel approaches that address haploinsufficiency disorders in a targeted and robust manner. Here, we developed a novel, modular tool for transcriptional regulation of genes involved in neurodevelopmental disease in the absence of creating double-stranded breaks. We utilized this novel platform technology to identify single guide RNA (sgRNAs) that efficiently regulate expression of the intellectual disability gene FOXG1 that utilizes an optimized protein intein system. Using a modular assembly of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) trans-activators, including single and dual VP64 (tetramer of herpes simplex virus VP16 peptide) dCas9 fusion proteins, sgRNA-mediated MS2 p65 HSF (MPH) recruitment or the addition of the VPR tripartite effector (VP64, p65, and Rta) can induce dynamic gene regulation. We further increased messenger RNA (mRNA) levels of FOXG1 using duplexed sgRNAs paired with different combinations of transcriptional activators. We demonstrate that FOXG1 gene upregulation results in a significant increase in FoxG1 protein translation. Following treatment of mutant FOXG1 neural stem cells with the CRISPR activators, we observed a significant increase in FOXG1 expression with no-off targets as determined by in silico sgRNA binding prediction paired with RNA-sequencing. This approach holds great promise as a modular platform technology that is readily adapted for gene therapy delivery for those affected by rare genetic conditions.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01MH103134

  NIH · $1.4M · 2017

• NIH Grant R56MH109587

  NIH · $376k · 2018

• High content assays for cellular and synaptic phenotypes

  NIH · $29.2M · 2021

• Investigating neurodevelopmental toxicity of perfluoroalkyl acids and their derivatives in human brain organoids models

  NIH · $3.0M · 2022–2026

• Integrative functional genomic study of pathways impacted by recurrent autism CNV

  NIH · $2.6M · 2016–2023

Frequent coauthors

• Cleber A. Trujillo

  Rady Children's Hospital-San Diego

  109 shared

• Roberto H. Herai

  Pontifícia Universidade Católica do Paraná

  83 shared

• Fred H. Gage

  Salk Institute for Biological Studies

  70 shared

• Priscilla D. Negraes

  University of California, San Diego

  67 shared

• Pinar Mesci

  58 shared

• Maria C. Marchetto

  University of California, San Diego

  57 shared

• Cassiano Carromeu

  48 shared

• Ángela Macia

  University of California, San Diego

  46 shared

Education

• Ph.D., Molecular and Computational Biology

  University of California, San Diego

  2006

• M.S., Molecular and Computational Biology

  University of California, San Diego

  2002

• B.S., Molecular and Computational Biology

  University of California, San Diego

  2000