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Gharpure, A.

Publications and source records attributed to Gharpure, A..

2 recordsLinked to original sources
bioRxiv2020

Intranasal Administration of Functionalized Soot Particles Disrupts Olfactory Sensory Neuron Progenitor Cells in the Neuroepithelium

Exposure to air pollution has been linked to the development of neurodegenerative diseases and anosmia, but the underlying mechanism is not known. Additionally, the loss of olfactory function often precedes the onset of neurodegenerative diseases. Chemical ablation of olfactory sensory neurons blocks the drainage of cerebrospinal fluid (CSF) through the cribriform plate and alters normal CSF production and/or circulation. Damage to this drainage pathway could contribute to the development of neurodegenerative diseases and could link olfactory sensory neuron health and neurodegeneration. Here, we investigated the impact of intranasal treatment of combustion products (laboratory-generated soots) and their oxygen functionalized derivatives on mouse olfactory sensory neurons, olfactory nerve cell progenitors, and the behavior of the mouse. We found that after a month of every-other-day intranasal treatment of soots, there was minimal effect on olfactory sensory neuron anatomy or exploratory behavior in the mouse. However, oxygen-functionalized soot caused a large decrease in globose basal cells, which are olfactory progenitor cells. These results suggest that exposure to air pollution damages the olfactory neuron progenitor cells, and could lead to decreases in the number of olfactory neurons, potentially disrupting CSF drainage.

neuroscience↗
bioRxiv2019

A functionally conserved mechanism of modulation via a vestibule site in pentameric ligand-gated ion channels

Pentameric ligand-gated ion channels (pLGICs) belong to a class of ion channels involved in fast synaptic signaling in the central and peripheral nervous systems. Molecules acting as allosteric modulators target binding sites that are remote from the neurotransmitter binding site, but functionally affect coupling of ligand binding to channel opening. Here, we investigated an allosteric binding site in the ion channel vestibule, which has converged from a series of studies on prokaryote and eukaryote channel homologs. We discovered single domain antibodies, called nanobodies, which are functionally active as allosteric modulators, and solved co-crystal structures of the prokaryote channel ELIC bound either to a positive (PAM) or a negative (NAM) allosteric modulator. We extrapolate the functional importance of the vestibule binding site to eukaryote ion channels, suggesting a conserved mechanism of allosteric modulation. This work identifies key elements of allosteric binding sites and extends drug design possibilities in pLGICs using nanobodies.

neuroscience↗