Aaron DiAntonio

Washington University in St. Louis

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Jeffrey Milbrandt

Washington University in St. Louis

Yo Sasaki

Washington University in St. Louis

Richard W. Daniels

University of Wisconsin–Madison

Amy Strickland

Washington University in St. Louis

A. Joseph Bloom

James S. McDonnell Foundation

Daniel W. Summers

University of Iowa

Xianrong Mao

Center for Neuro-Oncology

Catherine A. Collins

University of Michigan–Ann Arbor

Vera Valakh

Broad Institute

Jian Zhu

Soochow University

Cooperative Institutions

Washington University in St. Louis

191

Inserm

175

University of Michigan–Ann Arbor

165

Centre National de la Recherche Scientifique

156

Harvard University

150

National Institutes of Health

119

Howard Hughes Medical Institute

101

Washtenaw Community College

UiT The Arctic University of Norway

Istituti di Ricovero e Cura a Carattere Scientifico

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SARM1 is required in human derived sensory neurons for injury-induced and neurotoxic axon degeneration

Experimental Neurology (2021)

Yi‐Hsien Chen Yo Sasaki Aaron DiAntonio Jeffrey Milbrandt

Degeneration (medical)

Sensory neuron

10.1016/j.expneurol.2021.113636

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Citations (35)

FK506-binding protein-like and FK506-binding protein 8 regulate dual leucine zipper kinase degradation and neuronal responses to axon injury

Journal of Biological Chemistry (2022)

Bohm Lee Yeonsoo Oh Eunhye Cho Aaron DiAntonio Valeria Cavalli

The dual leucine zipper kinase (DLK) is a key regulator of axon regeneration and degeneration in response to neuronal injury; however, regulatory mechanisms of the DLK function via its interacting proteins are largely unknown. To better understand the molecular mechanism of DLK function, we performed yeast two-hybrid screening analysis and identified FK506-binding protein-like (FKBPL, also known as WAF-1/CIP1 stabilizing protein 39) as a DLK-binding protein. FKBPL binds to the kinase domain of DLK and inhibits its kinase activity. In addition, FKBPL induces DLK protein degradation through ubiquitin-dependent pathways. We further assessed other members in the FKBP protein family and found that FK506-binding protein 8 (FKBP8) also induced DLK degradation. We identified the lysine 271 residue in the kinase domain as a major site of DLK ubiquitination and SUMO3 conjugation and was thus responsible for regulating FKBP8-mediated proteasomal degradation that was inhibited by the substitution of the lysine 271 to arginine. FKBP8-mediated degradation of DLK is mediated by autophagy pathway because knockdown of Atg5 inhibited DLK destabilization. We show that in vivo overexpression of FKBP8 delayed the progression of axon degeneration and suppressed neuronal death after axotomy in sciatic and optic nerves. Taken together, this study identified FKBPL and FKBP8 as novel DLK-interacting proteins that regulate DLK stability via the ubiquitin-proteasome and lysosomal protein degradation pathways.

Protein Degradation

ASK1

10.1016/j.jbc.2022.101647

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Citations (10)

Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program

JCI Insight (2019)

Stefanie Geisler Ryan A. Doan Galen Cheng Aysel Cetinkaya‐Fisgin Shay X. Huang

Chemotherapy-induced peripheral neuropathy is one of the most prevalent dose-limiting toxicities of anticancer therapy. Development of effective therapies to prevent chemotherapy-induced neuropathies could be enabled by a mechanistic understanding of axonal breakdown following exposure to neuropathy-causing agents. Here, we reveal the molecular mechanisms underlying axon degeneration induced by 2 widely used chemotherapeutic agents with distinct mechanisms of action: vincristine and bortezomib. We showed previously that genetic deletion of SARM1 blocks vincristine-induced neuropathy and demonstrate here that it also prevents axon destruction following administration of bortezomib in vitro and in vivo. Using cultured neurons, we found that vincristine and bortezomib converge on a core axon degeneration program consisting of nicotinamide mononucleotide NMNAT2, SARM1, and loss of NAD+ but engage different upstream mechanisms that closely resemble Wallerian degeneration after vincristine and apoptosis after bortezomib. We could inhibit the final common axon destruction pathway by preserving axonal NAD+ levels or expressing a candidate gene therapeutic that inhibits SARM1 in vitro. We suggest that these approaches may lead to therapies for vincristine- and bortezomib-induced neuropathies and possibly other forms of peripheral neuropathy.

Wallerian degeneration

Chemotherapy-Induced Peripheral Neuropathy

10.1172/jci.insight.129920

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Citations (130)

SIK3 and Wnk converge on Fray to regulate glial K+ buffering and seizure susceptibility

PLoS Genetics (2023)

Lorenzo Lones Aaron DiAntonio

Glial cells play a critical role in maintaining homeostatic ion concentration gradients. Salt-inducible kinase 3 (SIK3) regulates a gene expression program that controls K+ buffering in glia, and upregulation of this pathway suppresses seizure behavior in the eag, Shaker hyperexcitability mutant. Here we show that boosting the glial SIK3 K+ buffering pathway suppresses seizures in three additional molecularly diverse hyperexcitable mutants, highlighting the therapeutic potential of upregulating glial K+ buffering. We then explore additional mechanisms regulating glial K+ buffering. Fray, a transcriptional target of the SIK3 K+ buffering program, is a kinase that promotes K+ uptake by activating the Na+/K+/Cl- co-transporter, Ncc69. We show that the Wnk kinase phosphorylates Fray in Drosophila glia and that this activity is required to promote K+ buffering. This identifies Fray as a convergence point between the SIK3-dependent transcriptional program and Wnk-dependent post-translational regulation. Bypassing both regulatory mechanisms via overexpression of a constitutively active Fray in glia is sufficient to robustly suppress seizure behavior in multiple Drosophila models of hyperexcitability. Finally, we identify cortex glia as a critical cell type for regulation of seizure susceptibility, as boosting K+ buffering via expression of activated Fray exclusively in these cells is sufficient to suppress seizure behavior. These findings highlight Fray as a key convergence point for distinct K+ buffering regulatory mechanisms and cortex glia as an important locus for control of neuronal excitability.

10.1371/journal.pgen.1010581

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Citations (3)

The role of integrins in Drosophila development

Cell Differentiation and Development (1989)

Michael Wilcox Maria Leptin Aaron DiAntonio

10.1016/0922-3371(89)90199-8

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Citations (1)

Dynamic regulation of SCG10 in regenerating axons after injury

Experimental Neurology (2013)

Jung Eun Shin Stefanie Geisler Aaron DiAntonio

Wallerian degeneration

Axotomy

Crush injury

Nerve Injury

Axoplasmic transport

10.1016/j.expneurol.2013.11.007

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Citations (174)

NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+ depletion

eLife (2016)

Yo Sasaki Takashi Nakagawa Xianrong Mao Aaron DiAntonio Jeffrey Milbrandt

Overexpression of the NAD+ biosynthetic enzyme NMNAT1 leads to preservation of injured axons. While increased NAD+ or decreased NMN levels are thought to be critical to this process, the mechanism(s) of this axon protection remain obscure. Using steady-state and flux analysis of NAD+ metabolites in healthy and injured mouse dorsal root ganglion axons, we find that rather than altering NAD+ synthesis, NMNAT1 instead blocks the injury-induced, SARM1-dependent NAD+ consumption that is central to axon degeneration.

Dorsal root ganglion

10.7554/elife.19749

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Citations (191)

Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival

Scientific Reports (2016)

Veronika Redmann Christopher A. Lamb Seungmin Hwang Robert C. Orchard Sung‐Su Kim

Abstract CLEC16A is in a locus genetically linked to autoimmune diseases including multiple sclerosis, but the function of this gene in the nervous system is unknown. Here we show that two mouse strains carrying independent Clec16a mutations developed neurodegenerative disease characterized by motor impairments and loss of Purkinje cells. Neurons from Clec16a -mutant mice exhibited increased expression of the autophagy substrate p62, accumulation of abnormal intra-axonal membranous structures bearing the autophagy protein LC3 and abnormal Golgi morphology. Multiple aspects of endocytosis, lysosome and Golgi function were normal in Clec16a-deficient murine embryonic fibroblasts and HeLa cells. However, these cells displayed abnormal bulk autophagy despite unimpaired autophagosome formation. Cultured Clec16a-deficient cells exhibited a striking accumulation of LC3 and LAMP-1 positive autolysosomes containing undigested cytoplasmic contents. Therefore Clec16a, an autophagy protein that is critical for autolysosome function and clearance, is required for Purkinje cell survival.

Autophagosome

10.1038/srep23326

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Citations (34)

Faculty Opinions recommendation of DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature (2013)

Aaron DiAntonio

10.3410/f.717986731.793472310

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Citations (0)

Genetic modifiers of abnormal organelle biogenesis in a Drosophila model of BLOC-1 deficiency

Human Molecular Genetics (2009)

Verónica T. Cheli Richard W. Daniels Ruth Godoy Diego J. Hoyle Vasundhara Kandachar

Biogenesis of lysosome-related organelles complex 1 (BLOC-1) is a protein complex formed by the products of eight distinct genes. Loss-of-function mutations in two of these genes, DTNBP1 and BLOC1S3, cause Hermansky–Pudlak syndrome, a human disorder characterized by defective biogenesis of lysosome-related organelles. In addition, haplotype variants within the same two genes have been postulated to increase the risk of developing schizophrenia. However, the molecular function of BLOC-1 remains unknown. Here, we have generated a fly model of BLOC-1 deficiency. Mutant flies lacking the conserved Blos1 subunit displayed eye pigmentation defects due to abnormal pigment granules, which are lysosome-related organelles, as well as abnormal glutamatergic transmission and behavior. Epistatic analyses revealed that BLOC-1 function in pigment granule biogenesis requires the activities of BLOC-2 and a putative Rab guanine-nucleotide-exchange factor named Claret. The eye pigmentation phenotype was modified by misexpression of proteins involved in intracellular protein trafficking; in particular, the phenotype was partially ameliorated by Rab11 and strongly enhanced by the clathrin-disassembly factor, Auxilin. These observations validate Drosophila melanogaster as a powerful model for the study of BLOC-1 function and its interactions with modifier genes.

Rab

Organelle biogenesis

Organelle

10.1093/hmg/ddp555

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Citations (63)