Biology subjects

Hogan, Q. H.

Publications and source records attributed to Hogan, Q. H..

3 recordsLinked to original sources

bioRxiv2023

Schwann cell release of p11 induces sensory neuron hyperactivity in Fabry disease.

Patients with Fabry disease suffer from chronic debilitating pain and peripheral sensory neuropathy with minimal treatment options, but the cellular drivers of this pain are unknown. Here, we propose a novel mechanism by which altered signaling between Schwann cells and sensory neurons underlies the peripheral sensory nerve dysfunction we observe in a genetic rat model of Fabry disease. Using in vivo and in vitro electrophysiological recordings, we demonstrate that Fabry rat sensory neurons exhibit pronounced hyperexcitability. Schwann cells likely contribute to this finding as application of mediators released from cultured Fabry Schwann cells induces spontaneous activity and hyperexcitability in naive sensory neurons. We examined putative algogenic mediators using proteomic analysis and found that Fabry Schwann cells release elevated levels of the protein p11 (S100-A10) which induces sensory neuron hyperexcitability. Removal of p11 from Fabry Schwann cell media causes hyperpolarization of neuronal resting membrane potential, indicating that p11 contributes to the excessive neuronal excitability caused by Fabry Schwann cells. These findings demonstrate that rats with Fabry disease exhibit sensory neuron hyperexcitability caused in part by Schwann cell release of the protein p11. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/542493v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1f672f1org.highwire.dtl.DTLVardef@f42f45org.highwire.dtl.DTLVardef@14b9806org.highwire.dtl.DTLVardef@1e9bee3_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Peripheral sensory neurons and non-neuronal cells express functional Piezo1 that is activated in peripheral nerve injury-induced neuropathic pain

This study reports that targeting intrinsically disordered regions (IDRs) of NaV1.7 protein facilitated discovery of sodium channel inhibitory peptide aptamers (NaviPA) for adeno-associated virus (AAV)-mediated, sensory neuron-specific analgesia. A multipronged inhibition of INa1.7, INa1.6, and INa1.3, but not INa1.5 and INa1.8 was found for a prototype, named NaviPA1, which was derived from the NaV1.7 intracellular loop 1 and is conserved among the TTXs NaV subtypes. NaviPA1 expression in primary sensory neurons (PSNs) of dorsal root ganglia (DRG) produced significant inhibition of TTXs INa but not TTXr INa. DRG injection of AAV6-encoded NaviPA1 significantly attenuated evoked and spontaneous pain behaviors in both male and female rats with neuropathic pain induced by tibial nerve injury (TNI). Whole-cell current-clamp of the PSNs showed that NaviPA1 expression normalized PSN excitability in TNI rats, suggesting that NaviPA1 attenuated pain by reversal of injury-induced neuronal hypersensitivity. Immunohistochemistry revealed efficient NaviPA1 expression restricted in PSNs and their central and peripheral terminals, indicating PSN-restricted AAV biodistribution. Inhibition of sodium channels by NaviPA1 was replicated in the human iPSC-derived sensory neurons. These results summate that NaviPA1 is a promising analgesic lead that, combined with AAV-mediated PSN-specific block of multiple TTXs NaVs has potential as peripheral nerve-restricted analgesic therapeutics.

neuroscience↗

bioRxiv2021

Piezo2 mechanosensitive ion channel is located to sensory neurons and non-neuronal cells in rat peripheral sensory pathway: implications in pain

Piezo2 mechanotransduction channel is a crucial mediator of sensory neurons for sensing and transducing touch, vibration, and proprioception. We here characterized Piezo2 expression and cell specificity in rat peripheral sensory pathway using a validated Piezo2 antibody. Immunohistochemistry using this antibody revealed Piezo2 expression in pan primary sensory neurons (PSNs) of dorsal rood ganglia (DRG) in naive rats, which was actively transported along afferent axons to both central presynaptic terminals innervating the spinal dorsal horn (DH) and peripheral afferent terminals in skin. Piezo2 immunoreactivity (IR) was also detected in the postsynaptic neurons of the DH and in the motor neurons of the ventral horn, but not in spinal GFAP- and Iba1-positive glia. Notably, Piezo2-IR was clearly identified in peripheral non-neuronal cells, including perineuronal glia, Schwann cells in the sciatic nerve and surrounding cutaneous afferent endings, as well as in skin epidermal Merkel cells and melanocytes. Immunoblots showed increased Piezo2 in DRG ipsilateral to plantar injection of complete Freunds adjuvant (CFA), and immunostaining revealed increased Piezo2-IR intensity in the DH ipsilateral to CFA injection. This elevation of DH Piezo2-IR was also evident in various neuropathic pain models and monosodium iodoacetate (MIA) knee osteoarthritis (OA) pain model, compared to controls. We conclude that 1) the pan neuronal profile of Piezo2 expression suggests that Piezo2 may function extend beyond simply touch/proprioception mediated by large-sized low-threshold mechanosensitive PSNs, 2) Piezo2 may have functional roles involving sensory processing in spinal cord, Schwann cells, and skin melanocytes, and 3) aberrant Piezo2 expression may contribute pain pathogenesis.

neuroscience↗