Jeffrey D Milbrandt
Washington University in St Louis, MO·Neuroscience
Axons are the long cables nerve cells use to reach muscles and skin, and when they break down people lose movement, sensation, or gain chronic pain. Axon loss is not passive decay: cells run an active self-destruct program, and a single enzyme called SARM1 is its main executioner.
- Fields
Neuroscience
Genetics
Biochemistry
- Topics
axon degeneration
Wallerian degeneration
NAD+
- Grants
- 5 known grants, through May 2029
What they work on
- Determine how regulatory ubiquitin tags, including those added by Parkin after mitochondrial damage, change the activity of SARM1, the NAD+-destroying enzyme that executes axon degeneration.
- Find new molecular regulators of SARM1 using kinase inhibitor panels and a CRISPR screen across all druggable genes, read out with a fluorescent sensor of SARM1 activity in models of low-level, chronic activation.
- Define how failed DNA repair activates SARM1-dependent axon degeneration, using human induced pluripotent stem cell-derived motor neuron models of ALS, and develop SARM1 activators as axon-specific non-opioid pain treatments.
- Characterize the immune and other cells infiltrating nerves in a mouse model of sarmopathy by transcriptional profiling, to determine their origin and identify genes shaping SARM1-driven neuroinflammation.
- Test whether repair Schwann cells and candidate chemoattractants and their receptors are required for SARM1-dependent macrophage recruitment, by crossing the NMNAT2-mutant neuropathy model with informative gene knockouts.
- Test the role of the phagocytic 'eat-me' lipid phosphatidylserine in axon elimination by manipulating it and its receptors in vivo, including viral overexpression of the lipase ABHD12 in mouse spinal cord.
- Explain why motor axons but not sensory axons degenerate when lactate dehydrogenase is lost, using a complementation assay in iPSC-derived neurons and mice lacking LDHA or LDHB in motor neurons, sensory neurons or Schwann cells.
- Determine whether damaging LDHB variants found in ALS patients are enriched relative to controls, using biochemical and cellular complementation assays, and test how impaired lactate/pyruvate metabolism accelerates disease in ALS mouse models.
- Build a single-nucleus atlas of human peripheral nerve using snRNA-seq, snATAC-seq, spatial transcriptomics and multiplex proteomics on donor tissue, and compare it with surgically resected painful neuromas to find cell-type-specific pain determinants.
- Develop CRANIUM, a platform reading genomic, transcriptional and neuronal phenotypic signatures of intellectual and developmental disability genes, to group rare mutations across more than 700 genes into shared disrupted pathways.
More about the research
Research here centers on that program — how SARM1 is switched on and restrained, how its activation recruits inflammatory cells that finish the job, how the metabolic fuel supplied by neighboring support cells keeps motor axons alive — and extends into two related problems: cataloguing the cell types of human peripheral nerve to find the molecular roots of chronic pain, and grouping the many rare mutations behind intellectual and developmental disabilities into shared pathways.
Why it matters
Axon loss underlies ALS, Charcot-Marie-Tooth disease, and diabetic and chemotherapy-induced peripheral neuropathy, conditions with few treatments. Identifying how SARM1 and the inflammation it triggers destroy axons could yield axon-protective, anti-inflammatory drugs, while deliberately activating SARM1 in pain-carrying axons is proposed as a non-opioid approach to localized chronic pain. A human nerve atlas and patient genome sequencing could explain why rodent-based pain drugs fail in people, and the CRANIUM platform could group rare developmental-disability mutations into pathways treatable in larger patient subsets.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Luke Judge
University of California-San Francisco, CA·Genetics
Test allele-specific genome editing against two different dominant CMT2E mutations and develop rigorous phenotypic assays of therapeutic benefit in motor neurons derived from patient-modeled human induced pluripotent stem cells.
Xin Chen
University of Texas Southwestern Medical Center, TX·Genetics
Test whether AAV9fyhr-delivered PDHA1, injected into the spinal fluid of E75A mice at several doses and at young or older ages, improves behavior and corrects metabolic measures in this model of pyruvate dehydrogenase complex deficiency.
Jefferson Matthew Taliaferro
University of Colorado Denver/Anschutz Medical Campus, CO·Biochemistry
Identify RNAs that are mislocalized in human stem-cell-derived motor neurons that lack TDP-43, carry ALS-linked TDP-43 mutations, or come from ALS patients, using a transcriptome-wide RNA mislocalization assay.
The school
Washington University in St Louis: 97 labs on PI Pages, $1.2B a year on research, 365 research doctorates a year.
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