About

Dr. Maria Carolina (Carol) Marchetto received her Ph.D. in microbiology from the University of São Paulo, Brazil, in 2005. She completed a five-year postdoctoral fellowship in neurobiology and neuroscience at The Salk Institute in La Jolla, California. Prior to her appointment at UC San Diego, Dr. Marchetto was a Staff Scientist at the laboratory of Genetics at The Salk Institute, where she led projects studying neuronal development using human and nonhuman primate stem cells. Her research focuses on using patient-derived induced pluripotent stem cells to investigate the cellular behavior of human neurons in neuropsychiatric and neurodevelopmental conditions such as Autism Spectrum Disorders. Additionally, her work explores human evolution in the context of brain expansion and neuronal development. She employs innovative stem cell models from human and nonhuman primate species to test hypotheses about the role of disruptions to human-specific cellular and molecular signatures in development and their potential impact on mental health, framed within our close evolutionary context. Her research is supported by grants from the National Institutes of Mental Health and private foundations. Dr. Marchetto offers undergraduate and graduate courses on using stem cell models to study evolution and neuropsychiatric conditions, the neuroscience of meditation, and ethical dilemmas in stem cell research. She is also developing a graduate seminar on the latest topics in stem cell research, evolution, and neuroscience.

Research topics

• Neuroscience
• Biology
• Medicine
• Internal medicine
• Genetics
• Immunology
• Cell biology
• Psychology

Selected publications

• Cell Density Impacts Population Activity in Human iPSC-Derived Neural Networks

  eNeuro · 2026-04-24

  articleOpen access

  Multi-electrode recording of neuronal activity in cultures offer opportunities for understanding how the structure of a network gives rise to function. Neuronal cultures derived from human induced pluripotent stem cells (iPSCs) from male and female individuals are often plated at highly variable cell densities across studies, but its impact on neuronal activity remains poorly understood. We found that properties such as the mean firing rate of the individual cells, the pairwise correlations between cells, and the entropy of the population all changed significantly with changes in culture density. We used a maximum entropy model to capture the structure of the population activity using only the firing rates and correlations, and we found that the model performed best at the highest densities, suggesting that changes in activity reflected differences in structure of interactions between neurons across scales of complexity. Our work thus shows that culture density is an important experimental parameter that impacts neuronal activity in human iPSC-derived cultures. Additionally, our findings provide an analytical framework to study population activity in neuronal cultures including those from patient populations where a disease process may impact network activity.

  PublisherOA PDFDOI

• CK2 inhibition suppresses glial inflammation in models of neuroinflammation and neurodegeneration

  Nature Communications · 2026-04-21

  articleOpen access

  Neuroinflammation plays a key role in Alzheimer’s disease (AD) and many other neurodegenerative disorders. Chronic activation of astrocytes and microglia fuels neuronal damage via cytokine secretion, oxidative stress, and proteolysis, yet glial inflammatory regulation remains poorly understood. Using chemoproteomics, we identified CK2, particularly the brain-enriched catalytic subunit CK2α2, as a key driver of astrocytic inflammation. CK2 enhances NF-κB activity by phosphorylating NF-κB S529 and IκBα S32, promoting pro-inflammatory gene expression. Genetic or chemical CK2 inhibition dampens inflammation, including IL-6 and IL-8 expression in a TNFα acute neuroinflammation mouse model. CK2α2 is upregulated in AD postmortem tissues and patient-derived astrocytes. AD astrocytes exhibit a hyperinflammatory state that can be attenuated by CK2 inhibition. Overexpression of CK2α2 in cortical organoids mimics AD pathology, whereas CK2 inhibition using the potent, selective, and brain-penetrant probe TAL606 rescues inflammatory markers in AD APP/PS1 mice. These findings position CK2 as a central regulator of neuroinflammation and a promising therapeutic target for AD and related disorders. Chemoproteomics coupled with patient-derived and organoid models identify and validate brain-enriched CK2α2 as an inflammatory driver in Alzheimer's disease. Blocking CK2 (including with brain-penetrant TAL606) lowers inflammatory signals in AD mice.

  PublisherDOI

• Human AUTS2 regulates neurodevelopmental pathways via dual DNA/RNA binding

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-08 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract The AUTS2 gene is implicated in neurodevelopmental and psychiatric disorders, with patient mutations leading to intellectual disability, microcephaly, and autistic behavior. While AUTS2’s chromatin-and RNA-related functions are recognized, its direct binding to RNA in human neural progenitors has not been previously demonstrated. Here, we used ChIP-seq and eCLIP-seq in human neural progenitor cells (NPCs) to map AUTS2’s chromatin targets and, for the first time, its direct RNA interactome. AUTS2 knockdown in NPCs led to widespread gene expression changes and impaired cell proliferation, migration, and neurite outgrowth. Integrated analysis revealed downregulation of Wnt pathway genes, notably WNT7A , among targets directly bound by AUTS2 at both chromatin and RNA levels. Supplementation with WNT7A rescued cellular phenotypes in AUTS2-deficient NPCs, underscoring the significance of Wnt signaling. These findings highlight AUTS2’s central role in human neurodevelopment and provide mechanistic insight into how its disruption may contribute to the pathology of neurodevelopmental disorders.

  PublisherOA PDFDOI

• AAV Kills Dividing Cells by Depleting PARP1 and Other DNA Damage Response Proteins

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-15 · 2 citations

  preprintOpen access

  Recombinant adeno-associated virus (rAAV) is a replication-defective viral vector used in hundreds of human gene therapy trials, resulting in five FDA-approved therapies. Despite this success, rAAV-based gene therapies suffer from dose-limiting toxicities, resulting in several severe adverse reactions, including death. Previously, we discovered that rAAV rapidly kills mouse NPCs in vitro and in vivo. This vector contains a minimal genome comprised of 145-base pair inverted terminal repeats (ITRs) with a T-shaped hairpin structure that appears to be necessary and sufficient for this toxicity. However, the mechanism for AAV ITR toxicity is not known, and there have been few attempts to engineer ITRs to attenuate rAAV toxicity. In the current study, we explore the molecular mechanisms that drive dose-dependent rAAV toxicity in dividing human NPCs (hNPCs) and test whether disrupting these mechanisms mitigates this toxicity. Recombinant AAV infection induces aberrant cell cycle progression with activation of the ATM /CHK1/CHK2 pathway and expression of the DNA damage markers γH2AX and 53BP1. Affinity-based proteomics indicate that AAV ITRs bind to Poly-(ADP-Ribose)polymerase 1 (PARP1) and other DNA damage response (DDR) proteins involved in single-strand break repair (SSBR). Recombinant AAV infection attenuates poly-(ADP-ribose) (PAR) formation and mimics the antiproliferative effects of pharmacological PARP inhibitors used in cancer therapy. Moreover, treatment of hNPCs with PARP inhibitors is sufficient to reproduce many features of rAAV-induced toxicity. Finally, we demonstrate that eliminating the T-shaped hairpin within the AAV ITR reduces binding to SSBR proteins and the resulting rAAV toxicity. These findings suggest that rAAV infection induces replication stress and cell death in dividing hNPCs by functionally depleting PARP1 and other DDR proteins that are essential for DNA replication. This work fills substantial gaps in the understanding of the mechanisms of rAAV toxicity and has important implications for the development of safer rAAV-based human gene therapies.

  PublisherOA PDFDOI

• Evolution of Human Susceptibility to Alzheimer's Disease: A Review of Hypotheses and Comparative Evidence

  Evolutionary Anthropology Issues News and Reviews · 2025-01-13 · 2 citations

  reviewOpen accessSenior authorCorresponding

  Primates rely on memory to navigate both physical and social environments and in humans, loss of memory function leads to devastating consequences. Alzheimer's disease (AD) is a neurodegenerative disease which begins by impacting memory functioning and is ultimately fatal. AD is common across human populations and its prevalence is predicted to rise with increases in the aging population. Despite this, the full AD phenotype has not been observed in any other nonhuman primate species. While a significant amount of research has been devoted to understanding the immediate mechanisms involved in AD pathogenesis in humans, less research has focused on why humans are particularly vulnerable to neurodegenerative diseases like AD. Here we explore hypotheses on the evolution of distinct human susceptibility to AD and place these in the context of findings from comparative neuroanatomical and molecular studies and discuss recent evidence for evolutionary changes protective against AD in the primate lineage.

  PublisherOA PDFDOI

• CK2 inhibition suppresses glial inflammation in the brain

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-07 · 1 citations

  preprintOpen access

  Neuroinflammation plays a key role in Alzheimer's disease (AD) and related neurodegenerative disorders. Chronic activation of astrocytes and microglia fuels neuronal damage via cytokine secretion, oxidative stress, and proteolysis. However, glial inflammatory regulation remains poorly understood. Using chemoproteomics, we identified CK2, particularly the brain-enriched catalytic subunit CK2α2, as a key driver of astrocytic inflammation. CK2 enhances NF-κB activity by phosphorylating NF-κB S529 and IκBα S32, promoting pro-inflammatory gene expression. CK2 inhibition via genetic or chemical approaches dampens inflammation, including IL-6 and IL-8 expression in an acute neuroinflammation mouse model. CK2α2 is upregulated in AD postmortem tissues and patient-derived astrocytes. AD astrocytes exhibit a hyperinflammatory state that can be attenuated by CK2 inhibition. Overexpression of CK2α2 in cortical organoids mimics AD pathology, whereas CK2 inhibition using the potent, selective, and brain-penetrant probe TAL606 rescues inflammatory markers in transgenic AD mice. These findings position CK2 as a central regulator of neuroinflammation and a promising therapeutic target for AD and related disorders.

  PublisherOA PDFDOI

• Exploring mood disorders and treatment options using human stem cells

  Genetics and Molecular Biology · 2024-01-01 · 2 citations

  articleOpen accessSenior author

  Despite their global prevalence, the mechanisms for mood disorders like bipolar disorder and major depressive disorder remain largely misunderstood. Mood stabilizers and antidepressants, although useful and effective for some, do not have a high responsiveness rate across those with these conditions. One reason for low responsiveness to these drugs is patient heterogeneity, meaning there is diversity in patient characteristics relating to genetics, etiology, and environment affecting treatment. In the past two decades, novel induced pluripotent stem cell (iPSC) research and technology have enabled the use of human-derived brain cells as a new model to study human disease that can help account for patient variance. Human iPSC technology is an emerging tool to better understand the molecular mechanisms of these disorders as well as a platform to test novel treatments and existing pharmaceuticals. This literature review describes the use of iPSC technology to model bipolar and major depressive disorder, common medications used to treat these disorders, and novel patient-derived alternative treatment methods for non-responders stemming from past publications, as well as presenting new data derived from these models.

  PublisherOA PDFDOI

• HPR11 The Horizon of Oncology: Estimating the Impact of New EU Regulation on Health Technology Assessment for 2025-2028

  Value in Health · 2024-12-01

  articleOpen access
  PublisherOA PDFDOI

• Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

  Molecular Psychiatry · 2024-05-04 · 21 citations

  articleOpen access

  Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. To address the question of how and when concordance in monozygotic twins occur, we have obtained fibroblasts from two pairs of schizophrenia discordant twins (one sibling with schizophrenia while the second one is unaffected by schizophrenia) and three pairs of healthy twins (both of the siblings are healthy). We have prepared iPSC models for these 3 groups of patients with schizophrenia, unaffected co-twins, and the healthy twins. When the study started the co-twins were considered healthy and unaffected but both the co-twins were later diagnosed with a depressive disorder. The reprogrammed iPSCs were differentiated into hippocampal neurons to measure the neurophysiological abnormalities in the patients. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. Importantly, their synaptic activity was not affected. Our measurements that were obtained from schizophrenia patients and their monozygotic twin and compared also to control healthy twins point to hippocampal synaptic deficits as a central mechanism in schizophrenia.

  PublisherOA PDFDOI

• Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

  Molecular Psychiatry · 2023-03-29 · 27 citations

  articleOpen access

  Abstract Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list ( P hypergeometric = 1.28E–09 and 4.10E–18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

  PublisherOA PDFDOI

Recent grants

• Transcriptional signature profiling of IGF1-treated neural cells from idiopathic autistic patients

  NIH · $96k · 2018–2020

• Transcriptional signature profiling of IGF1-treated neural cells from idiopathic autistic patients

  NIH · $96k · 2018–2020

Frequent coauthors

• Fred H. Gage

  Salk Institute for Biological Studies

  74 shared

• Renata Santos

  Universidade Federal do Rio Grande do Norte

  65 shared

• Alysson R. Muotri

  University of California, San Diego

  57 shared

• Carlos Frederico Martins Menck

  Universidade de São Paulo

  20 shared

• Joseph R. Calabrese

  University School

  14 shared

• Shani Stern

  University of Haifa

  13 shared

• Kristen Brennand

  12 shared

• Keming Gao

  Case Western Reserve University

  12 shared

Labs

• Biological Anthropology LabsPI

Awards & honors

• $1.2M by Hillblom Foundation to study brain aging, dementia