Functional Role of the Interaction between Polysialic Acid and Extracellular Histone H1

Abstract

Polysialic acid (PSA) is a large and highly negatively charged glycan that plays crucial roles in nervous system development and function in the adult. It has been suggested to facilitate cell migration, neurite outgrowth, and synaptic plasticity because its hydration volume could enhance flexibility of cell interactions. Evidence for receptors of PSA has so far been elusive. We now identified histone H1 as binding partner of PSA via a single-chain variable fragment antibody using an anti-idiotypic approach. Histone H1 directly binds to PSA as shown by ELISA. Surface biotinylation of cultured cerebellar neurons indicated an extracellular localization of histone H1. Immunostaining of live cerebellar neurons and Schwann cells confirmed that an extracellular pool of histone H1 colocalizes with PSA at the cell surface. Histone H1 was also detected in detergent-insoluble synaptosomal membrane subfractions and postsynaptic densities. When applied in vitro, histone H1 stimulated neuritogenesis, process formation and proliferation of Schwann cells, and migration of neural precursor cells via a PSA-dependent mechanism, further indicating that histone H1 is active extracellularly. These in vitro observations suggested an important functional role for the interaction between histone H1 and PSA not only for nervous system development but also for regeneration in the adult. Indeed, histone H1 improved functional recovery, axon regrowth, and precision of reinnervation of the motor branch in adult mice with femoral nerve injury. Our findings encourage investigations on the therapeutic potential of histone H1 in humans.

Extracellular histone H1 is neurotoxic and drives a pro-inflammatory response in microglia

“…Histone H1 greatly increased the numbers of astrocytes with a stellate morphology when applied at concentrations as low as 15 nM ( Figure 7). These observations are consistent with a previous report 23 and we went on to look at the effects of histone H1 on microglia that mediate the innate immune response of the central nervous system (CNS).…”

Functional Role of the Interaction between Polysialic Acid and Myristoylated Alanine-rich C Kinase Substrate at the Plasma Membrane

“…Affinity Chromatography with a PSA Mimicking Anti-idiotypic Antibody-Propagation and screening of the phage library as well as selection, purification, and characterization of PSAmimicking single chain variable fragment (scFv) antibody was performed as described (9). For the preparation of soluble brain proteins, 15 brains from postnatal (0 -7 days old) or adult (12-16 weeks old) C57BL/6J mice were homogenized in 4 ml of TNE buffer (25 mM Tris-HCl, pH 7.5, 150 mM NaCl, 5 mM EDTA).…”

“…In a recent study we used a PSA-mimicking anti-idiotypic scFv antibody for immunoaffinity chromatography with a mouse brain fraction enriched in membrane-associated proteins and identified histone H1 as a novel PSA binding partner (9). Here, we applied soluble brain proteins isolated from postnatal or adult mice to the immobilized PSA-mimicking scFv antibody.…”

Histones facilitate α-synuclein aggregation during neuronal apoptosis

“…Evidence suggests that histones can be secreted into extracellular fluids from a range of cell types, including neurons [1], glia [28] and some activated immune cells [35,9,2] in response to cell stress. Moreover, extracellular histones are significantly elevated in response to brain injury [4,20], which is a risk factor for PD [3,10].…”