About

Nancy M. Bonini is the Florence R.C. Murray Professor of Biology at the University of Pennsylvania. She holds secondary faculty appointments in Cell & Developmental Biology and Neuroscience at the Perelman School of Medicine. Her research interests encompass Neurobiology, Behavior, and Physiology, as well as Genetics, Epigenetics, Genomics, and Cell and Developmental Biology. Professor Bonini's work integrates these fields to advance understanding of biological processes related to nervous system function and genetic regulation.

Research topics

• Genetics
• Biology
• Medicine
• Pathology
• Psychiatry
• Neuroscience
• Surgery
• Computational biology

Selected publications

• Multiomic single nuclei profiling the mouse hippocampus reveals that ACSS2 confers neuronal resilience to tauopathy

  Alzheimer s & Dementia · 2026-02-01 · 1 citations

  articleOpen access

  INTRODUCTION: Epigenomic dysregulation contributes to Alzheimer's disease (AD) and related tauopathies. Acetyl-CoA synthetase 2 (ACSS2), a nuclear-localized metabolic enzyme in neurons, supports histone acetylation and learning-related gene expression. We examined how ACSS2 loss affects molecular and behavioral phenotypes in a mouse model of tauopathy. METHODS: We induced tauopathy in ACSS2 knockout and control mice via injection of pathological human tau. We assessed transcriptomic, epigenomic, and behavioral changes, and tested long-term acetate supplementation as a rescue strategy. RESULTS: ACSS2 loss worsened tau-seeding-related phenotypes, particularly in hippocampal pyramidal neurons and Cajal-Retzius cells. Acetate supplementation rescued learning in an ACSS2-dependent manner and restored gene expression linked to cognition. DISCUSSION: ACSS2 acts as a neuroprotective metabolic enzyme in vulnerable hippocampal neurons, and targeting this pathway through dietary supplementation may offer therapeutic potential for AD and related tauopathies. HIGHLIGHTS: We combine tau seeding with deletion of acetyl-CoA synthetase 2 (ACSS2) to test this enzyme in an Alzheimer's disease model. Loss of ACSS2 exacerbates transcriptional and behavioral responses to tau injection. We observe robust transcriptional dysregulation in pyramidal neurons in the hippocampus. We observe reduced numbers of reelin-producing Cajal-Retzius cells in the hippocampus. Acetate supplementation rescues transcriptional and behavioral responses to tau.

  PublisherOA PDFDOI

• ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration

  Proceedings of the National Academy of Sciences · 2026-01-09 · 1 citations

  articleOpen accessCorresponding

  Epigenetic mechanisms, including histone acetylation, regulate learning and memory and underlie Alzheimer's disease and related dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme generating acetyl-CoA, locally regulates histone acetylation and gene expression in neuronal nuclei. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously, we showed that systemic ACSS2 knockout mice, although largely normal in physiology, exhibit memory deficits. Here, we investigated whether increasing ACSS2 levels could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology and the P301S transgenic mouse model for tau-induced memory decline. Our results show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Additionally, boosting histone acetylation through ACSS2 countered age-related memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. These findings position ACSS2 as a key epigenetic regulator of cognitive aging and ADRD, highlighting its potential for targeted therapeutics to enhance brain resilience and function.

  PublisherDOI

• Peripheral metabolic dysfunction drives sleep disruption in TDP-43 proteinopathy

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-24 · 1 citations

  articleOpen access

  Abstract Sleep disruption is an early and prevalent feature of neurodegenerative disease, commonly attributed to neuronal circuit dysfunction or cell loss. However, sleep is tightly coupled to metabolic state, raising the possibility that systemic metabolic abnormalities contribute to disease-associated sleep phenotypes. Using Drosophila models of TDP-43 proteinopathy, we investigated whether peripheral metabolic dysfunction plays a causal role in sleep disruption. We show that TDP-43 expression induces a chronic, starvation-like metabolic state characterized by depletion of peripheral carbohydrate stores despite normal feeding. Restoration of sleep fails to correct these metabolic defects, whereas improving peripheral metabolic state robustly rescues sleep. A modifier screen of ∼650 RNAi lines identified Salt-inducible kinase 3 (SIK3) as a potent suppressor of both sleep loss and starvation sensitivity. Transcriptomic and spatial metabolomic analyses reveal that SIK3 selectively remodels a peripheral metabolic program centered on the pentose phosphate pathway and redox-associated metabolites without globally restoring energy stores. Together, these findings identify systemic metabolic dysfunction as a key driver of sleep disruption in TDP-43 proteinopathy and highlight peripheral metabolism as a potential therapeutic entry point for sleep dysfunction in neurodegenerative disease.

  PublisherDOI

• A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system

  Cell Death and Disease · 2026-05-13

  articleOpen access

  RNA-binding proteins (RBPs) play an essential role in development, normal functioning, and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire human STAU1 gene (hSTAU1) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum, and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes, and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene.

  PublisherOA PDFDOI

• A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system

  Research Square · 2025-09-23

  preprintOpen access
  PublisherOA PDFDOI

• Senescent glia link mitochondrial dysfunction and lipid accumulation

  Nature · 2024-06-05 · 115 citations

  articleOpen accessSenior author

  Abstract Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species 1,2 . Acutely, senescent cells promote wound healing 3,4 and prevent tumour formation 5 ; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy 6–11 , why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear 12,13 . Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence 14,15 , we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.

  PublisherOA PDFDOI

• Author Correction: Senescent glia link mitochondrial dysfunction and lipid accumulation

  Nature · 2024-08-07 · 2 citations

  erratumOpen accessSenior author
  PublisherOA PDFDOI

• TDP-43 impairs sleep in <i>Drosophila</i> through <i>Ataxin-2</i> –dependent metabolic disturbance

  Science Advances · 2024-01-10 · 14 citations

  articleOpen accessCorresponding

  Neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia are associated with substantial sleep disruption, which may accelerate cognitive decline and brain degeneration. Here, we define a role for trans-activation response element (TAR) DNA binding protein 43 (TDP-43), a protein associated with human neurodegenerative disease, in regulating sleep using Drosophila . Expression of TDP-43 severely disrupts sleep, and the sleep deficit is rescued by Atx2 knockdown. Brain RNA sequencing revealed that Atx2 RNA interference regulates transcripts enriched for small-molecule metabolic signaling in TDP-43 brains. Focusing on these Atx2 -regulated genes, we identified suppressors of the TDP-43 sleep phenotype enriched for metabolism pathways. Knockdown of Atx2 or treatment with rapamycin attenuated the sleep phenotype and mitigated the disruption of small-molecule glycogen metabolism caused by TDP-43. Our findings provide a connection between toxicity of TDP-43 and sleep disturbances and highlight key aspects of metabolism that interplay with TDP-43 toxicity upon Atx2 rescue.

  PublisherOA PDFDOI

• Cell type‐specific regulation of<scp>m⁶A</scp>modified<scp>RNAs</scp>in the aging<i>Drosophila</i>brain

  Aging Cell · 2024-01-11 · 9 citations

  articleOpen accessSenior authorCorresponding

  Abstract The aging brain is highly vulnerable to cellular stress, and neurons employ numerous mechanisms to combat neurotoxic proteins and promote healthy brain aging. The RNA modification m 6 A is highly enriched in the Drosophila brain and is critical for the acute heat stress response of the brain. Here we examine m 6 A in the fly brain with the chronic stresses of aging and degenerative disease. m 6 A levels dynamically increased with both age and disease in the brain, marking integral neuronal identity and signaling pathway transcripts that decline in level with age and disease. Unexpectedly, there is opposing impact of m 6 A transcripts in neurons versus glia, which conferred different outcomes on animal health span upon Mettl3 knockdown to reduce m 6 A: whereas Mettl3 function is normally beneficial to neurons, it is deleterious to glia. Moreover, knockdown of Mettl3 in glial tauopathy reduced tau pathology and increased animal survival. These findings provide mechanistic insight into regulation of m 6 A modified transcripts with age and disease, highlighting an overall beneficial function of Mettl3 in neurons in response to chronic stresses, versus a deleterious impact in glia.

  PublisherOA PDFDOI

• ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-29 · 1 citations

  preprintOpen accessCorresponding

  ABSTRACT Epigenetic mechanisms, including histone acetylation, are pivotal for learning and memory, with a role in neuronal function in Alzheimer’s disease and Related Dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme that generates acetyl-CoA, is central to histone acetylation and gene regulation, particularly in neurons, due to their unique metabolic demands and postmitotic state. ACSS2 can be recruited to the nucleus and chromatin, locally supplying acetyl-CoA to directly fuel histone acetyltransferase enzymes and key neuronal gene expression. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously we showed that systemic ACSS2 deletion in mice, although largely normal in physiology, is greatly impaired in memory. Here we investigated whether increasing ACSS2 levels could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology and the P301S transgenic mouse model for tau-induced memory decline. Our results show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Expanding upon these findings, we reveal that increasing histone acetylation through ACSS2 upregulation improves age-associated memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. We thus highlight ACSS2 as a key player in the epigenetic regulation of cognitive aging and ADRD, providing a foundation for targeted therapeutics to enhance brain resilience and function. Summary ACSS2 upregulation protects neurons from disease and age-related decline by enhancing synaptic and longevity gene expression.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R29EY011259

  NIH · $569k · 2002

• NIH Grant P01AG009215

  NIH · $16.3M · 2011

• NIH Grant R01NS043578

  NIH · $1.3M · 2010

• NIH Grant R01NS066312

  NIH · $1.2M · 2014

• NIH Grant R01NS078283

  NIH · $3.3M · 2018

Frequent coauthors

• Bradley R. Cairns

  University of Utah

  49 shared

• Craig C. Mello

  Howard Hughes Medical Institute

  49 shared

• Matthew L. Warman

  Boston Children's Hospital

  49 shared

• T Lahn

  Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa

  49 shared

• Sean Eddy

  University of Michigan–Ann Arbor

  49 shared

• Jeannie T. Lee

  Harvard University

  49 shared

• Kexiang Xu

  California University of Pennsylvania

  32 shared

• Aaron D. Gitler

  Stanford University

  32 shared

Education

• B.S., Biology

  University of Pennsylvania

  1982

• Ph.D., Molecular and Cell Biology

  University of California, San Francisco

  1987

Awards & honors

• NIH Outstanding Investigator R35 Award (2016)
• Glenn Award for Research in the Biological Mechanisms of Agi…
• Member of the American Academy of Arts and Sciences, since 2…
• Member of the National Academy of Medicine, since 2012
• Member of the National Academy of Sciences, since 2012