About

David Wassarman is a Professor of Medical Genetics at the University of Wisconsin–Madison. His laboratory focuses on understanding the role that genetic variation plays in determining outcomes of traumatic brain injury. His research encompasses disease biology, cell biology, development, gene expression, genomics and proteomics, neuro and behavioral genetics, and Drosophila research. Wassarman's work aims to elucidate mechanisms underlying neurodegeneration, with particular attention to how genetic factors influence traumatic brain injury outcomes. His contributions include investigating the effects of specific mutations on brain injury responses in Drosophila models, advancing knowledge in neurogenetics and the genetic basis of neurodegenerative processes.

Research topics

• Genetics
• Medicine
• Biology
• Immunology
• Internal medicine
• Cancer research
• Anesthesia
• Physiology
• Cell biology
• Neuroscience
• Psychiatry

Selected publications

• ImageJ Cell Quantification Macro

  Open MIND · 2026-01-01 · 1 citations

  articleOpen accessSenior author

  ImageJ macro developed in the Wassarman Laboratory for automated batch quantification of fluorescent microscopy images, outputting per-image cell count and size data.

  PublisherOA PDFDOI

• Genetic variation in innate immune gene expression influences mortality after traumatic brain injury in <i>Drosophila</i>

  G3 Genes Genomes Genetics · 2026-03-13

  articleOpen accessSenior author

  Traumatic brain injury (TBI) is a leading cause of disability and death, with outcome severity varying widely even among individuals with comparable injuries. A major challenge is to identify pathways that underlie this variation and could be targeted to improve therapies. Innate immune pathways are candidates because they are rapidly activated after TBI and contribute to neurodegenerative disorders. Using a Drosophila melanogaster TBI model, we examined how genetic background, age, and diet modify effects of evolutionarily conserved Toll and Immune deficiency (Imd) pathways on injury outcomes. These pathways signal through nuclear factor-kappa B (NF-κB) transcription factors Dorsal-related immunity factor (Dif) and Relish (Rel) to activate antimicrobial peptide (AMP) gene expression. We found that genetic diversity among lines from the Drosophila Genetic Reference Panel (DGRP) contributed to variation in AMP expression before and after TBI, with additional effects of age and diet. AMP expression tended to be correlated positively with early mortality following TBI in young flies, but negatively in older flies, suggesting an age-dependent shift in AMP effects from detrimental to protective. Furthermore, heterozygous mutations in Dif or Rel lowered AMP expression in a diet-dependent manner and led to correspondingly reduced early mortality after TBI. These findings show that genetic, biological, and environmental factors influence innate immune pathways, which in turn determine TBI outcomes. Innate immune gene expression before injury emerges as a potential prognostic indicator, pointing to potential new therapeutic strategies.

  PublisherDOI

• Aging influences nucleolar responses to traumatic brain injury in Drosophila

  PLoS ONE · 2025-11-03

  articleOpen accessSenior authorCorresponding

  Traumatic brain injury (TBI) affects millions of people globally each year, yet effective treatments remain limited. A major challenge is the complexity of cellular and molecular responses to brain injury, many of which overlap with those seen in aging. A key hallmark of aging is nucleolar enlargement in brain and other tissues, reflecting increased ribosome biogenesis. Nucleolar size is regulated by the target of rapamycin (TOR) signaling pathway, which during aging is aberrantly activated. Inhibiting TOR reduces nucleolar size and extends lifespan in several model organisms. Using a Drosophila melanogaster model of closed-head TBI, we investigated whether injury influences nucleolar dynamics. Immunofluorescence microscopy of fibrillarin, a major nucleolar protein, revealed that brains of young, injured flies had substantially larger nucleoli than uninjured controls within one day of injury. Over the following weeks, the difference gradually diminished as nucleolar size increased in uninjured flies, eventually matching that of injured flies, which remained relatively stable. Additionally, heterogeneity in nucleolar size across cells became more pronounced with injury and aging. Finally, injury of older flies resulted in little or no nucleolar enlargement and even shrinkage within a few days of injury. These results suggest that TBI and aging converge on shared mechanisms that regulate nucleolar size, which may reach a maximal limit through either process. Consistent with this, mortality at 24 hours post-injury in young flies was significantly reduced by pharmacological inhibition of TOR with rapamycin or RapaLink-1, indicating that nucleolar enlargement contributes to TBI-induced damage. Overall, our results suggest that TBI accelerates the aging-associated increase in nucleolar size, implicating elevated ribosome biogenesis in TBI pathogenesis and highlighting TOR inhibition as a promising therapeutic approach.

  PublisherDOI

• Traumatic brain injury reprograms lipid droplet metabolism shaped by aging and diet in Drosophila brain

  PLoS ONE · 2025-09-12 · 2 citations

  articleOpen accessSenior authorCorresponding

  Traumatic brain injury (TBI) initiates secondary cellular damage such as mitochondrial dysfunction, oxidative stress, and neuroinflammation. In neurodegenerative disorders, these stressors are associated with accumulation of lipid droplets (LDs) - organelles that store neutral lipids to provide energy and protect cells from lipid toxicity. However, the regulation of LD metabolism following TBI remains poorly understood. Using a Drosophila melanogaster model, we investigated how TBI influences LD accumulation, particularly in relation to aging and diet, other LD modulatory factors. Confocal microscopy of fly brains at one day after injury showed increases in both LD size and number. The rise in LD number occurred only in flies fed a carbohydrate-rich diet and was absent in those given a ketogenic diet (KD) or water, suggesting that glucose availability is necessary for LD formation post-injury and potentially underlying why KD and water do not elicit the deleterious outcomes observed with carbohydrates. Lipidomic analysis of fly heads further revealed elevated levels of triacylglycerol (TG) species typically stored in LDs, indicating enhanced lipid synthesis post-injury. By seven days post-injury, LD size and number returned to baseline levels observed in uninjured flies and remained stable through 14 days post-injury. However, by 21 days post-injury, uninjured flies showed a marked increase in LD number that was not observed in injured flies, although LD size increased in both groups. These findings suggest that TBI selectively impairs age-dependent production of new LDs without affecting the growth of existing LDs. Importantly, TG levels remained elevated in heads of injured flies, indicating that the reduction in LD number was not due to limited lipid availability. Together, our findings indicate that TBI acutely induces LD formation as a protective response but chronically impairs LD biogenesis, disrupting lipid homeostasis in an age- and diet-dependent manner that may contribute to neurodegeneration.

  PublisherDOI

• Traumatic brain injury induces DNA damage in Drosophila

  PubMed · 2025-07-21

  articleOpen accessSenior author

  (fruit fly) TBI model to investigate when DNA damage occurs following injury and whether age at the time of injury affects its severity. Using a Comet assay, which quantifies DNA damage in individual cells, we found that damage in the brain occurred within 4 hours of injury in both young and older flies. Levels of damage remained stable in young flies at 6 hours post-injury, but increased in older flies, indicating that aging processes enhance the post-TBI DNA damage mechanism. Although DNA damage initially resolved within 24 hours of injury; likely through DNA repair, loss of damaged cells, or death of flies with damage; it reappeared weeks later, revealing a previously unrecognized second phase of genomic instability following TBI. These findings establish Drosophila as a valuable model for studying TBI-induced DNA damage, a model that offers powerful genetic tools to investigate underlying mechanisms and to test whether genetic background affects the severity of DNA damage and contributes to individual variation in TBI outcomes.

  PublisherOA PDFDOI

• Expansion of Electron Transport Chain Mutants That Cause Anesthetic-Induced Toxicity in Drosophila melanogaster

  Oxygen · 2024-03-02 · 1 citations

  articleOpen access

  The mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places individuals with mETC mutations at risk for anesthetic complications, as exemplified by patients with Leigh syndrome (LS). The Drosophila melanogaster homozygous mutant for ND-23, which encodes a subunit of mETC Complex I, replicates numerous characteristics of LS, including neurodegeneration, shortened lifespan, behavioral anesthetic hypersensitivity, and toxicity. The anesthetic phenotype of toxicity (lethality) is also observed in flies homozygous for mutations in other Complex I subunits. By contrast, mutations conferring sensitivity have not yet been identified for subunits of Complexes II–V. Furthermore, anesthetic phenotypes are thought to be recessive; that is, risk is not conferred by heterozygous mutations. However, at older ages, exposure of heterozygous mutant ND-23 flies to the VGA isoflurane in 75% oxygen (hyperoxia) results in toxicity. It is also unknown whether combinations of heterozygous mutations in different subunits of the mETC can result in anesthetic toxicity. Here, we show that, following exposure to isoflurane in hyperoxia, flies carrying heterozygous mutations in two Complex I subunits, ND-23 and ND-SGDH (NADH dehydrogenase (ubiquinone) SGDH subunit), had a level of anesthetic toxicity that exceeded the added toxicities of the individual heterozygous mutations. In addition, we show that flies heterozygous for two different alleles of the Complex II gene SdhB were susceptible to isoflurane/hyperoxia-induced anesthetic toxicity. Finally, a mutation in the SdhC subunit of Complex II of Caenorhabditis elegans resulted in isoflurane-induced mortality, supporting the role of Complex II in anesthetic toxicity. These data expand the landscape of mutations in the mETC that increase sensitivity to anesthetic toxicity.

  PublisherOA PDFDOI

• Links between mutations in functionally separate arms of mitochondrial complex I and responses to volatile anesthetics

  Pediatric Anesthesia · 2024-09-27 · 1 citations

  articleOpen access

  BACKGROUND: Individuals with mitochondrial defects, especially those in Complex I of the electron transport chain, exhibit behavioral hypersensitivity and toxicity to volatile anesthetics. In Drosophila melanogaster, mutation of ND23 (NDUFS8 in mammals), which encodes a subunit of the matrix arm of Complex I, sensitizes flies to toxicity from isoflurane but not an equipotent dose of sevoflurane. Also, in ND23 flies, both anesthetics activate expression of stress response genes, but to different extents. Here, we investigated the generality of these findings by examining flies mutant for ND2 (ND2 in mammals), which encodes a subunit of the membrane arm of Complex I. METHODS: flies to precise doses of isoflurane, sevoflurane, and oxygen. Behavioral sensitivity was assessed by a climbing assay and toxicity by percent mortality within 24 h of exposure. Changes in expression were determined by qRT-PCR of RNA isolated from heads at 0.5 h after anesthetic exposure. RESULTS: flies. Finally, the mutations had different effects on induction of stress response gene expression by the anesthetics. CONCLUSION: Mutations in different arms of Complex I resulted in different behavioral sensitivities and toxicities to isoflurane and sevoflurane, indicating that (i) the anesthetics have mechanisms of action that involve arms of Complex I to different extents and (ii) the lack of behavioral hypersensitivity does not preclude susceptibility to anesthetic toxicity.

  PublisherOA PDFDOI

• Genetic Differences Modify Anesthetic Preconditioning of Traumatic Brain Injury in Drosophila

  Journal of Neurotrauma · 2024-11-19 · 1 citations

  articleOpen accessCorresponding

  Pre-clinical vertebrate models of traumatic brain injury (TBI) routinely use anesthetics for animal welfare; however, humans experience TBI without anesthetics. Therefore, translation of findings from vertebrate models to humans hinges on understanding how anesthetics influence cellular and molecular events that lead to secondary injuries following TBI. To investigate the effects of anesthetics on TBI outcomes, we used an invertebrate Drosophila melanogaster model to compare outcomes between animals exposed or not exposed to anesthetics prior to the same primary injury. Using a common laboratory fly line, w 1118 , we found that exposure to the volatile anesthetics isoflurane or sevoflurane, but not ether, prior to TBI produced a dose-dependent reduction in mortality within 24 h following TBI. Thus, isoflurane and sevoflurane precondition w 1118 flies to deleterious effects of TBI. To examine the effects of genetic differences on anesthetic preconditioning of TBI, we repeated the experiment with the Drosophila Genetic Reference Panel (DGRP) collection of genetically diverse, inbred fly lines. Pre-exposure to either isoflurane or sevoflurane revealed a wide range of preconditioning levels among 171 and 144 DGRP lines, respectively, suggesting a genetic component for variation in anesthetic preconditioning of mortality following TBI. Finally, genome-wide association study analyses identified single-nucleotide polymorphisms in genes associated with isoflurane or sevoflurane preconditioning of TBI. Several of the genes, including the fly ortholog of mammalian Calcium Voltage-Gated Subunit Alpha1 D ( CACNA1D ), are highly expressed in neurons and are functionally linked to both anesthetics and TBI. These data indicate that anesthetic dose and genetic background should be considered when investigating effects of anesthetics in vertebrate TBI models, and they support use of the fly model for elucidating the mechanisms underlying anesthetic preconditioning of TBI.

  PublisherOA PDFDOI

• <i>Lissencephaly-1</i> mutations enhance traumatic brain injury outcomes in <i>Drosophila</i>

  Genetics · 2023-01-23 · 8 citations

  articleOpen accessSenior authorCorresponding

  Traumatic brain injury (TBI) outcomes vary greatly among individuals, but most of the variation remains unexplained. Using a Drosophila melanogaster TBI model and 178 genetically diverse lines from the Drosophila Genetic Reference Panel (DGRP), we investigated the role that genetic variation plays in determining TBI outcomes. Following injury at 20-27 days old, DGRP lines varied considerably in mortality within 24 h ("early mortality"). Additionally, the disparity in early mortality resulting from injury at 20-27 vs 0-7 days old differed among DGRP lines. These data support a polygenic basis for differences in TBI outcomes, where some gene variants elicit their effects by acting on aging-related processes. Our genome-wide association study of DGRP lines identified associations between single nucleotide polymorphisms in Lissencephaly-1 (Lis-1) and Patronin and early mortality following injury at 20-27 days old. Lis-1 regulates dynein, a microtubule motor required for retrograde transport of many cargoes, and Patronin protects microtubule minus ends against depolymerization. While Patronin mutants did not affect early mortality, Lis-1 compound heterozygotes (Lis-1x/Lis-1y) had increased early mortality following injury at 20-27 or 0-7 days old compared with Lis-1 heterozygotes (Lis-1x/+), and flies that survived 24 h after injury had increased neurodegeneration but an unaltered lifespan, indicating that Lis-1 affects TBI outcomes independently of effects on aging. These data suggest that Lis-1 activity is required in the brain to ameliorate TBI outcomes through effects on axonal transport, microtubule stability, and other microtubule proteins, such as tau, implicated in chronic traumatic encephalopathy, a TBI-associated neurodegenerative disease in humans.

  PublisherOA PDFDOI

• Stress Pathways Induced by Volatile Anesthetics and Failure of Preconditioning in a Mitochondrial Complex I Mutant

  Anesthesiology · 2023-12-20 · 5 citations

  articleOpen access

  BACKGROUND: Carriers of mutations in the mitochondrial electron transport chain are at increased risk of anesthetic-induced neurotoxicity. To investigate the neurotoxicity mechanism and to test preconditioning as a protective strategy, this study used a Drosophila melanogaster model of Leigh syndrome. Model flies carried a mutation in ND23 (ND2360114) that encodes a mitochondrial electron transport chain complex I subunit. This study investigated why ND2360114 mutants become susceptible to lethal, oxygen-modulated neurotoxicity within 24 h of exposure to isoflurane but not sevoflurane. METHODS: This study used transcriptomics and quantitative real-time reverse transcription polymerase chain reaction to identify genes that are differentially expressed in ND2360114 but not wild-type fly heads at 30 min after exposure to high- versus low-toxicity conditions. This study also subjected ND2360114 flies to diverse stressors before isoflurane exposure to test whether isoflurane toxicity could be diminished by preconditioning. RESULTS: The ND2360114 mutation had a greater effect on isoflurane- than sevoflurane-mediated changes in gene expression. Isoflurane and sevoflurane did not affect expression of heat shock protein (Hsp) genes (Hsp22, Hsp27, and Hsp68) in wild-type flies, but isoflurane substantially increased expression of these genes in ND2360114 mutant flies. Furthermore, isoflurane and sevoflurane induced expression of oxidative (GstD1 and GstD2) and xenobiotic (Cyp6a8 and Cyp6a14) stress genes to a similar extent in wild-type flies, but the effect of isoflurane was largely reduced in ND2360114 flies. In addition, activating stress response pathways by pre-exposure to anesthetics, heat shock, hyperoxia, hypoxia, or oxidative stress did not suppress isoflurane-induced toxicity in ND2360114 mutant flies. CONCLUSIONS: Mutation of a mitochondrial electron transport chain complex I subunit generates differential effects of isoflurane and sevoflurane on gene expression that may underlie their differential effects on neurotoxicity. Additionally, the mutation produces resistance to preconditioning by stresses that protect the brain in other contexts. Therefore, complex I activity modifies molecular and physiologic effects of anesthetics in an anesthetic-specific manner.

  PublisherOA PDFDOI

Recent grants

• Genetic Analysis of Neurodegeneration in Drosophila

  NIH · $1.6M · 2014–2019

• A Fly Model of Traumatic Brain Injury

  NIH · $421k · 2016–2018

• NIH Grant R21NS085302

  NIH · $404k · 2015

• TBI and aging in a Drosophila model

  NIH · $2.8M · 2019–2024

• Drosophila TAF1 as a Model for Signal-dependent Alternative Splicing

  NSF · $512k · 2008–2011

Frequent coauthors

• Rebeccah J. Katzenberger

  University of Wisconsin–Madison

  35 shared

• Barry Ganetzky

  University of Wisconsin–Madison

  29 shared

• Gerald M. Rubin

  Howard Hughes Medical Institute

  27 shared

• Misha Perouansky

  University of Wisconsin–Madison

  26 shared

• Zachariah P. G. Olufs

  University of Wisconsin–Madison

  23 shared

• Marc Therrien

  Institute for Research in Immunology and Cancer

  18 shared

• Frank Sauer

  Qserve Group (Netherlands)

  16 shared

• Lori A. Pile

  Wayne State University

  16 shared

Labs

• Laboratory of GeneticsPI

Education

• Ph.D., Genetics

  University of Wisconsin–Madison

  1992

• M.S., Genetics

  University of Wisconsin–Madison

  1988

• B.S., Genetics

  University of Wisconsin–Madison

  1985