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Squalamine Restores the Function of the Enteric Nervous System in Mouse Models of Parkinson’s Disease

Version 3 2024-06-03, 04:10
Version 2 2024-05-31, 04:55
Version 1 2024-05-28, 05:35
journal contribution
posted on 2024-06-03, 04:10 authored by Christine L West, Yu-Kang Mao, Thilini Delungahawatta, Jessica Y Amin, Sohana Farhin, Rachel M McQuade, Shanti Diwakarla, Ruslan Pustovit, Andrew M Stanisz, John Bienenstock, Denise Barbut, Michael Zasloff, John FurnessJohn Furness, Wolfgang A Kunze
Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder thought to be caused by accumulation of α-synuclein (α-syn) within the brain, autonomic nerves, and the enteric nervous system (ENS). Involvement of the ENS in PD often precedes the onset of the classic motor signs of PD by many years at a time when severe constipation represents a major morbidity. Studies conducted in vitro and in vivo, have shown that squalamine, a zwitterionic amphipathic aminosterol, originally isolated from the liver of the dogfish shark, effectively displaces membrane-bound α-syn. Objective: Here we explore the electrophysiological effect of squalamine on the gastrointestinal (GI) tract of mouse models of PD engineered to express the highly aggregating A53T human α-syn mutant. Methods: GI motility and in vivo response to oral squalamine in PD model mice and controls were assessed using an in vitro tissue motility protocol and via fecal pellet output. Vagal afferent response to squalamine was measured using extracellular mesenteric nerve recordings from the jejunum. Whole cell patch clamp was performed to measure response to squalamine in the myenteric plexus. Results: Squalamine effectively restores disordered colonic motility in vivo and within minutes of local application to the bowel. We show that topical squalamine exposure to intrinsic primary afferent neurons (IPANs) of the ENS rapidly restores excitability. Conclusion: These observations may help to explain how squalamine may promote gut propulsive activity through local effects on IPANs in the ENS, and further support its possible utility in the treatment of constipation in patients with PD.

History

Journal

Journal of Parkinson's Disease

Volume

10

Pagination

1477-1491

Location

Amsterdam, The Netherlands

ISSN

1877-7171

eISSN

1877-718X

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Issue

4

Publisher

IOS Press