About

Erika L.F. Holzbaur, Ph.D., is the William Maul Measey Professor in Physiology at the University of Pennsylvania's Perelman School of Medicine. Her laboratory focuses on microtubule-based motor proteins, particularly cytoplasmic dynein and its activator dynactin, which are essential for vesicular trafficking, microtubule organization, mitotic spindle assembly, and cellular polarity. Her research investigates the mechanisms of force production and motor function, cargo coupling and regulation, and the effects of dynein and dynactin on cytoskeletal dynamics. She is also interested in understanding how impairments in dynein/dynactin function contribute to neurodegenerative diseases, including motor neuron degeneration and muscle atrophy, which are similar to ALS. Her approaches include in vitro motility assays, biochemical and cellular assays, live cell microscopy, and the development of transgenic mouse models for motor neuron disease.

Research topics

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

Selected publications

• Pathogenic KIF1A variants differentially disrupt axonal trafficking and impede synaptic development

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-14

  articleOpen accessSenior authorCorresponding

  ABSTRACT The nervous system relies on billions of neurons connected through trillions of synapses to support a vast array of vital functions. Despite the critical importance of this synaptic network, the cellular mechanisms dictating synapse formation during human neurodevelopment remain unclear. Long-distance trafficking of synaptic components is critical for both synaptogenesis and the maintenance of synaptic function across lifespan. The microtubule motor KIF1A has a highly conserved role in the trafficking of synaptic vesicle precursors, while mutations in KIF1A are causal for the neurodevelopmental and neurodegenerative disease KIF1A -Associated Neurological Disorder (KAND). Here, we employ isogenic human induced pluripotent stem cells (iPSCs) gene-edited to express pathogenic KIF1A variants to assess how disparate mutations alter synaptic trafficking and function. We compared the effects of both loss-of-function and gain-of-function mutations on KIF1A motor activity. We found that both null (p.C92*) and hypoactive (p.P305L) mutations induce delayed neurite outgrowth, mislocalization of synaptic cargos, and decreased synapse density. Conversely, the hyperactive KIF1A mutation (p.R350G) supports neurite outgrowth but leads to aberrant motility of synaptic vesicle precursors along the axon. Further, live imaging reveals that hyperactive KIF1A induces deficits in the microtubule-dependent patterning of presynaptic components along the developing axon, suggesting a failure to respond to cytoskeletal cues directing cargo delivery. Functional analysis of neuronal activity via multi-electrode arrays reveals delayed synaptic maturation in loss-of-function mutations (p.P305L, p.C92*). In contrast, the hyperactive p.R350G mutation exhibits accelerated activity maturation and possible excitotoxicity. Together, these data provide insights detailing how pathogenic variants in KIF1A causative for KAND exhibit distinct effects at the molecular level that lead to significant downstream deficits in synaptic function in human neurons.

  PublisherDOI

• PINK1/Parkin-dependent mitophagy mediates astrocytic inflammatory responses to mitochondrial damage

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-13

  articleOpen accessSenior authorCorresponding

  ABSTRACT Astrocytes directly influence neuronal survival and increasingly are understood to contribute to the progression of neurodegenerative diseases including Parkinson’s disease (PD). Mitochondrial damage is a hallmark of PD pathology in both neurons and astrocytes. Damaged mitochondria are cleared by PINK1/Parkin-mediated mitophagy; loss-of-function mutations in either PINK1 or Parkin are sufficient to cause PD. Neuronal mitophagy is well-studied, but far less is known about how mitochondrial dysfunction in astrocytes affects neural health. While microglial release of pro-inflammatory cytokines has been shown to induce astrocytes to mount their own inflammatory response, we hypothesize that a more direct pathway is involved, and that mitochondrial damage to astrocytes directly triggers release of proinflammatory cytokines. To address these questions, we treated primary murine cortical astrocytes with oxidative phosphorylation (OXPHOS) inhibitors antimycin A (AA) and oligomycin A (OA) and observed the PINK1-dependent accumulation of Parkin on damaged mitochondria, leading to phospho-ubiquitination of proteins in the outer mitochondrial membrane and the recruitment of the autophagy receptor SQSTM1/p62. To identify transcriptional changes caused by mitochondrial damage and the resulting activation of mitophagic machinery, we performed bulk RNA-sequencing on astrocytes isolated from WT, PINK1 -/- , or Parkin -/- mice treated with AA/OA or a vehicle control. In WT astrocytes, TNF-α signaling via NF-κB was the most significantly upregulated pathway following OXPHOS inhibition. OXPHOS inhibitor treatment also stimulated p62 expression, while NF-κB inhibition prevented this upregulation. Astrocytic secretion of cytokines, including TNF-α, was increased following mitochondrial damage; this secretion was dependent on NF-κB activation and occurred at levels sufficient to induce mitochondrial depolarization in hippocampal neurons. Compared to WT astrocytes, PINK1 -/- astrocytes showed a significant reduction in transcriptional signatures associated with TNF-α signaling following mitochondrial damage, while Parkin -/- astrocytes exhibited upregulation of both IFN-γ and IFN-α signaling. These findings indicate altered inflammatory responses to mitochondrial damage in the absence of functional PINK1 or Parkin. Finally, we analyzed scRNA-sequencing data from substantia nigra astrocytes harvested from human brain tissue from PD-positive or control samples. Distinct clusters comprised predominantly of PD-positive or control astrocytes emerged. Astrocytes in the PD-positive cluster were enriched for NF-κB, IFN-α and IFN-γ responses, consistent with the signaling observed in vitro post-OXPHOS inhibition. Together, these findings identify inflammatory signatures activated by mitochondrial damage in astrocytes, and establish this pathway as a potential contributor to neuroinflammation in PD.

  PublisherDOI

• Autophagic stress activates distinct compensatory secretory pathways in neurons

  Proceedings of the National Academy of Sciences · 2025-07-07 · 16 citations

  articleOpen accessSenior authorCorresponding

  Autophagic dysfunction is a hallmark of neurodegenerative disease, leaving neurons vulnerable to the accumulation of damaged organelles and aggregated proteins. However, the late onset of diseases suggests that compensatory quality control mechanisms may be engaged to delay these deleterious effects. Neurons expressing common familial Parkinson’s disease-associated mutations in the leucine-rich repeat kinase 2 (LRRK2) exhibit defective autophagy. Here, we demonstrate that both primary murine neurons and human induced Pluripotent Stem Cells (iPSC)-derived neurons harboring pathogenic LRRK2 upregulate the secretion of extracellular vesicles. We used unbiased proteomics to characterize the secretome of LRRK2 G2019S neurons and found that autophagic cargos including mitochondrial proteins were enriched. Based on these observations, we hypothesize that autophagosomes are rerouted toward secretion when cell-autonomous degradation is compromised to mediate clearance of undegraded cellular waste. Immunoblotting confirmed the release of autophagic cargos and live-cell imaging demonstrated that secretory autophagy is upregulated in LRRK2 G2019S neurons. We also found that LRRK2 G2019S neurons upregulate the release of exosomes containing microRNAs. Live-cell imaging confirmed that this upregulation of exosomal release is dependent on hyperactive LRRK2 activity, while pharmacological experiments indicate that this release staves off apoptosis. Finally, we show that markers of both vesicle populations are upregulated in plasma from mice expressing pathogenic LRRK2. In sum, we find that neurons expressing pathogenic LRRK2 upregulate secretory autophagy and the compensatory release of exosomes to mediate waste disposal and transcellular communication, respectively. We propose that this increased secretion contributes to the maintenance of cellular homeostasis, delaying neurodegenerative disease progression over the short term while potentially contributing to neuroinflammation over the longer term.

  PublisherOA PDFDOI

• Lysosomal pH detection assay v1

  2025-06-20

  preprintOpen accessSenior author

  Detection of lysosomal pH in live cortical neurons.

  PublisherOA PDFDOI

• Isolate Crude EVs by Ultracentrifugation v1

  2025-05-09

  preprintOpen accessSenior author

  Protocol describing isolation of large (P20) and small (P100) extracellular vesicles isolated from primary mouse neurons. Protocol is used in "Autophagic stress activates distinct compensatory secretory pathways in neurons" by Palumbos et al., 2025

  PublisherOA PDFDOI

• CalceinAM labeling of Extracellular Vesicles v1

  2025-05-23

  preprintOpen accessSenior author

  Protocol used to visualize intact vesicles isolated from primary murine neurons. Protocol used in Palumbos et al., 2025 and adapted from https://doi.org/10.1371/journal.pone.0317689

  PublisherOA PDFDOI

• Primary cortical neuron nucleofection Amaxa Lonza v1

  2025-05-16

  preprintOpen accessSenior author

  Protocol to nucleofect primary murine cortical neurons. Protocol used in Palumbos et al., 2025 Protocol is adapted from protocol provided by LONZA- "Amaxa mouse neuron nucleofector kit."

  PublisherOA PDFDOI

• Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis

  Journal of Molecular Biology · 2025-04-21 · 26 citations

  reviewOpen accessSenior author

  Mitochondrial quality control is instrumental in regulating neuronal health and survival. The receptor-mediated clearance of damaged mitochondria by autophagy, known as mitophagy, plays a key role in controlling mitochondrial homeostasis. Mutations in genes that regulate mitophagy are causative for familial forms of neurological disorders including Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). PINK1/Parkin-dependent mitophagy is the best studied mitophagy pathway, while more recent work has brought to light additional mitochondrial quality control mechanisms that operate either in parallel to or independent of PINK1/Parkin mitophagy. Here, we discuss our current understanding of mitophagy mechanisms operating in neurons to govern mitochondrial homeostasis. We also summarize progress in our understanding of the links between mitophagic dysfunction and neurodegeneration, and highlight the potential for therapeutic interventions to maintain mitochondrial health and neuronal function.

  PublisherDOI

• Immunoprecipitation from primary neurons v1

  2025-06-30

  preprintOpen accessSenior author

  Protocol for immunoprecipitating proteins from neuronal lysates

  PublisherOA PDFDOI

• Protein Extraction, Mass Spectrometry, and Data Analysis v1

  2025-05-09

  preprintOpen accessSenior author

  Protocol describing protocol of protein extraction, mass spectrometry, and subsequent data analysis for Palumbos et al., 2025. All steps of the protocol were performed by CHOP PENN Proteomics core.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01GM068591

  NIH · $1.2M · 2009

• Mechanistic analysis of axonal transport defects in neurodegenerative disease

  NIH · $2.5M · 2018–2021

• NIH Grant P01GM087253

  NIH · $27.0M · 2020

• The Interaction of Cytoplasmic Dynein and Dynactin

  NIH · $7.4M · 1993–2019

• Molecular Mechanisms of Axonal Transport and Organelle Dynamics

  NIH · $5.6M · 2018–2028

Frequent coauthors

• Olivia Harding

  Aligning Science Across Parkinson's

  73 shared

• Mariko Tokito

  University of Pennsylvania

  49 shared

• Elisabeth Holzer

  Max Perutz Labs

  46 shared

• Julia F. Riley

  45 shared

• Sascha Martens

  Vienna Biocenter

  44 shared

• Yale E. Goldman

  30 shared

• C. Alexander Boecker

  Research Network (United States)

  28 shared

• Chantell S. Evans

  Duke University

  26 shared

Labs

• Holzbaur LabPI