VSIG4 interaction with heparan sulfates inhibits VSIG4-complement binding.

V-set and immunoglobulin domain-containing 4 (VSIG4) is a complement receptor of the immunoglobulin superfamily that is specifically expressed on tissue resident macrophages, and its many reported functions and binding partners suggest a complex role in immune function. VSIG4 is reported to have a role in immune surveillance as well as in modulating diverse disease phenotypes such as infections, autoimmune conditions, and cancer. However, the mechanism(s) governing VSIG4's complex, context-dependent role in immune regulation remains elusive. Here, we identify cell surface and soluble glycosaminoglycans, specifically heparan sulfates, as novel binding partners of VSIG4. We demonstrate that genetic deletion of heparan sulfate synthesis enzymes or cleavage of cell-surface heparan sulfates reduced VSIG4 binding to the cell surface. Furthermore, binding studies demonstrate that VSIG4 interacts directly with heparan sulfates, with a preference for highly sulfated moieties and longer glycosaminoglycan chains. To assess the impact on VSIG4 biology, we show that heparan sulfates compete with known VSIG4 binding partners C3b and iC3b. Furthermore, mutagenesis studies indicate that this competition occurs through overlapping binding epitopes for heparan sulfates and complement on VSIG4. Together these data suggest a novel role for heparan sulfates in VSIG4-dependent immune modulation.

Mutant TDP-43 Causes Early-Stage Dose-Dependent Motor Neuron Degeneration in a TARDBP Knockin Mouse Model of ALS.

Rare mutations in TARDBP, the gene encoding TDP-43, cause amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is seen in a large majority of ALS patients, suggesting a central pathogenic role of this regulatory protein. The consequences of TARDBP mutations on TDP-43 function and the mechanism by which mutant TDP-43 causes neurodegeneration remain uncertain. Here, we characterize a series of knockin mice carrying disease-associated TARDBP mutations. We demonstrate that TDP-43M337V and TDP-43G298S are functional, each rescuing the lethality of TDP-43 loss of function. In a subset of aged heterozygous knockin mice, we observe the earliest signs of selective motor neuron degeneration, demonstrating that physiological levels of mutant TDP-43 are sufficient to initiate disease. Furthermore, aged homozygous mutants develop selective, asymmetric motor neuron pathology, providing in vivo evidence of TDP-43 dose-dependent neurotoxicity. These knockin mice represent a faithful in vivo model of early-stage ALS and enable future exploration of TDP-43-associated neurodegeneration.

A model of toxic neuropathy in Drosophila reveals a role for MORN4 in promoting axonal degeneration.

Axonal degeneration is a molecular self-destruction cascade initiated following traumatic, toxic, and metabolic insults. Its mechanism underlies a number of disorders including hereditary and diabetic neuropathies and the neurotoxic side effects of chemotherapy drugs. Molecules that promote axonal degeneration could represent potential targets for therapy. To identify such molecules, we designed a screening platform based on intoxication of Drosophila larvae with paclitaxel (taxol), a chemotherapeutic agent that causes neuropathy in cancer patients. In Drosophila, taxol treatment causes swelling, fragmentation, and loss of axons in larval peripheral nerves. This axonal loss is not due to apoptosis of neurons. Taxol-induced axonal degeneration in Drosophila shares molecular execution mechanisms with vertebrates, including inhibition by both NMNAT (nicotinamide mononucleotide adenylyltransferase) expression and loss of wallenda/DLK (dual leucine zipper kinase). In a pilot RNAi-based screen we found that knockdown of retinophilin (rtp), which encodes a MORN (membrane occupation and recognition nexus) repeat-containing protein, protects axons from degeneration in the presence of taxol. Loss-of-function mutants of rtp replicate this axonal protection. Knockdown of rtp also delays axonal degeneration in severed olfactory axons. We demonstrate that the mouse ortholog of rtp, MORN4, promotes axonal degeneration in mouse sensory axons following axotomy, illustrating conservation of function. Hence, this new model can identify evolutionarily conserved genes that promote axonal degeneration, and so could identify candidate therapeutic targets for a wide-range of axonopathies.