The thrombin receptor links brain derived neurotrophic factor to neuron cholesterol production, resiliency and repair after spinal cord injury.
Animals
Brain-Derived Neurotrophic Factor
/ metabolism
Cholesterol
/ metabolism
Female
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Nerve Regeneration
/ physiology
Neuronal Outgrowth
/ physiology
Neurons
/ metabolism
Receptor, PAR-1
/ metabolism
Recovery of Function
/ physiology
Spinal Cord Injuries
/ metabolism
Journal
Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
16
09
2020
revised:
13
01
2021
accepted:
03
02
2021
pubmed:
8
2
2021
medline:
4
1
2022
entrez:
7
2
2021
Statut:
ppublish
Résumé
Despite concerted efforts to identify CNS regeneration strategies, an incomplete understanding of how the needed molecular machinery is regulated limits progress. Here we use models of lateral compression and FEJOTA clip contusion-compression spinal cord injury (SCI) to identify the thrombin receptor (Protease Activated Receptor 1 (PAR1)) as an integral facet of this machine with roles in regulating neurite growth through a growth factor- and cholesterol-dependent mechanism. Functional recovery and signs of neural repair, including expression of cholesterol biosynthesis machinery and markers of axonal and synaptic integrity, were all increased after SCI in PAR1 knockout female mice, while PTEN was decreased. Notably, PAR1 differentially regulated HMGCS1, a gene encoding a rate-limiting enzyme in cholesterol production, across the neuronal and astroglial compartments of the intact versus injured spinal cord. Pharmacologic inhibition of cortical neuron PAR1 using vorapaxar in vitro also decreased PTEN and promoted neurite outgrowth in a cholesterol dependent manner, including that driven by suboptimal brain derived neurotrophic factor (BDNF). Pharmacologic inhibition of PAR1 also augmented BDNF-driven HMGCS1 and cholesterol production by murine cortical neurons and by human SH-SY5Y and iPSC-derived neurons. The link between PAR1, cholesterol and BDNF was further highlighted by demonstrating that the deleterious effects of PAR1 over-activation are overcome by supplementing cultures with BDNF, cholesterol or by blocking an inhibitor of adenylate cyclase, Gαi. These findings document PAR1-linked neurotrophic coupling mechanisms that regulate neuronal cholesterol metabolism as an important component of the machinery regulating CNS repair and point to new strategies to enhance neural resiliency after injury.
Identifiants
pubmed: 33549720
pii: S0969-9961(21)00043-7
doi: 10.1016/j.nbd.2021.105294
pmc: PMC8021459
mid: NIHMS1670620
pii:
doi:
Substances chimiques
Brain-Derived Neurotrophic Factor
0
Receptor, PAR-1
0
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
105294Subventions
Organisme : NINDS NIH HHS
ID : R01 NS052741
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS120877
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS107946
Pays : United States
Organisme : NINDS NIH HHS
ID : R56 NS114117
Pays : United States
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
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