Next Article in Journal
Mycoplasma genitalium Infection and Chronic Inflammation in Human Prostate Cancer: Detection Using Prostatectomy and Needle Biopsy Specimens
Next Article in Special Issue
ATG-18 and EPG-6 are Both Required for Autophagy but Differentially Contribute to Lifespan Control in Caenorhabditis elegans
Previous Article in Journal
ROR1 Expression and Its Functional Significance in Hepatocellular Carcinoma Cells
Previous Article in Special Issue
Presenilins and γ-Secretase in Membrane Proteostasis
Article Menu
Issue 3 (March) cover image

Export Article

Open AccessArticle
Cells 2019, 8(3), 211;

Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo

Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, 55128 Mainz, Germany
Author to whom correspondence should be addressed.
Received: 29 January 2019 / Revised: 25 February 2019 / Accepted: 27 February 2019 / Published: 2 March 2019
(This article belongs to the Special Issue Proteostasis and Autophagy)
PDF [2513 KB, uploaded 2 March 2019]


Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer’s disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration. View Full-Text
Keywords: sigma-1 receptor; autophagy; proteostasis; neurodegeneration; C. elegans sigma-1 receptor; autophagy; proteostasis; neurodegeneration; C. elegans

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Share & Cite This Article

MDPI and ACS Style

Christ, M.G.; Huesmann, H.; Nagel, H.; Kern, A.; Behl, C. Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo. Cells 2019, 8, 211.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Cells EISSN 2073-4409 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top