The Sigma-1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models

Naia, Luana; Ly, Philip T. T.; Mota, Sandra I.; Lopes, Carla; Maranga, Carina; Coelho, Patrícia; Gershoni-Emek, Noga; Ankarcrona, Maria; Geva, Michal; Hayden, Michael R.; Rego, A. Cristina

doi:10.1007/s13311-021-01022-9

Cited by 30 publications

(30 citation statements)

References 68 publications

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“…In particular, it appears that central pattern generators involve: (i) motoneurons that activate muscle; (ii) ipsilateral excitatory interneurons that provide excitatory drive; (iii) inhibitory commissural interneurons that ensure left-right alternation; and (iv) ipsilateral inhibitory interneurons that contribute to burst termination [61]. S1R is highly expressed in motoneurons [62], and S1R activity has been shown to protect motoneurons from insults or neurodegeneration [15,[63][64][65]. Furthermore, S1R is expressed in interneurons [66] and alteration of S1R activity directly impacts interneurons activity.…”

Section: Discussionmentioning

confidence: 99%

Sigma-1 Receptor Is Critical for Mitochondrial Activity and Unfolded Protein Response in Larval Zebrafish

Crouzier

Denus

Richard

et al. 2021

IJMS

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The sigma-1 receptor (S1R) is a highly conserved transmembrane protein highly enriched in mitochondria-associated endoplasmic reticulum (ER) membranes, where it interacts with several partners involved in ER-mitochondria Ca2+ transfer, activation of the ER stress pathways, and mitochondria function. We characterized a new S1R deficient zebrafish line and analyzed the impact of S1R deficiency on visual, auditory and locomotor functions. The s1r+25/+25 mutant line showed impairments in visual and locomotor functions compared to s1rWT. The locomotion of the s1r+25/+25 larvae, at 5 days post fertilization, was increased in the light and dark phases of the visual motor response. No deficit was observed in acoustic startle response. A critical role of S1R was shown in ER stress pathways and mitochondrial activity. Using qPCR to analyze the unfolded protein response genes, we observed that loss of S1R led to decreased levels of IRE1 and PERK-related effectors and increased over-expression of most of the effectors after a tunicamycin challenge. Finally, S1R deficiency led to alterations in mitochondria bioenergetics with decreased in basal, ATP-linked and non-mitochondrial respiration and following tunicamycin challenge. In conclusion, this new zebrafish model confirmed the importance of S1R activity on ER-mitochondria communication. It will be a useful tool to further analyze the physiopathological roles of S1R.

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Section: Discussionmentioning

confidence: 99%

Sigma-1 Receptor Is Critical for Mitochondrial Activity and Unfolded Protein Response in Larval Zebrafish

Crouzier

Denus

Richard

et al. 2021

IJMS

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“…Pridopidine has shown protective effects on several mitochondrial functions in various human and mouse models of HD. In primary HD neurons, pridopidine enhances mitochondria-ER tethering and restores mitochondrial function as measured by increased ATP production, respiration, and mitochondrial membrane potential [126]. All these effects are exquisitely mediated by the activation of the S1R, as either a genetic deletion of the S1R or a pharmacological inhibition using an S1R antagonist, completely abolishes pridopidine's neuroprotective effects, as shown in the studies mentioned above [126].…”

Section: The S1r As a Therapeutic Target For The Treatment Of Neurodegenerative Diseasesmentioning

confidence: 94%

Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

Zhemkov

Geva²,

Hayden

et al. 2021

IJMS

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The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R modulates the activity of multiple effector proteins, but its signaling functions are poorly understood. S1R is associated with cholesterol, and in our recent studies we demonstrated that S1R association with cholesterol induces the formation of S1R clusters. We propose that these S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited and retained in these microdomains. This hypothesis is consistent with the results of an unbiased screen for S1R-interacting partners, which we performed using the engineered ascorbate peroxidase 2 (APEX2) technology. We further propose that S1R agonists enable the disassembly of these cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, signaling receptors, and trophic factors from the ER. This hypothesis may explain the pleotropic signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various experimental systems.

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“…A PET scan study of human HD patients also showed complete Sigmar1 occupancy by pridopidine ( Grachev et al, 2020 ; Battista et al, 2021 ), and the neuroprotective effects of pridopidine were abolished in Sigmar1 knockout mice ( Francardo et al, 2019 ). Activation of Sigmar1 by pridopidine rescued mitochondrial dysfunction induced by oxidative damage in YAC128 transgenic mice, human HD lymphoblasts, and human HD neural stem cells (NSCs) ( Naia et al, 2021 ). Moreover, early pridopidine treatment was effective in delaying onset of HD-related motor symptoms in YAC128 HD mice ( Naia et al, 2021 ).…”

Section: Physiological and Pathological Role Of Sigmar1mentioning

confidence: 99%

“…Activation of Sigmar1 by pridopidine rescued mitochondrial dysfunction induced by oxidative damage in YAC128 transgenic mice, human HD lymphoblasts, and human HD neural stem cells (NSCs) ( Naia et al, 2021 ). Moreover, early pridopidine treatment was effective in delaying onset of HD-related motor symptoms in YAC128 HD mice ( Naia et al, 2021 ).…”

Section: Physiological and Pathological Role Of Sigmar1mentioning

confidence: 99%

Sigmar1’s Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology

et al. 2021

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The Sigma 1 receptor (Sigmar1) is a ubiquitously expressed multifunctional inter-organelle signaling chaperone protein playing a diverse role in cellular survival. Recessive mutation in Sigmar1 have been identified as a causative gene for neuronal and neuromuscular disorder. Since the discovery over 40 years ago, Sigmar1 has been shown to contribute to numerous cellular functions, including ion channel regulation, protein quality control, endoplasmic reticulum-mitochondrial communication, lipid metabolism, mitochondrial function, autophagy activation, and involved in cellular survival. Alterations in Sigmar1’s subcellular localization, expression, and signaling has been implicated in the progression of a wide range of diseases, such as neurodegenerative diseases, ischemic brain injury, cardiovascular diseases, diabetic retinopathy, cancer, and drug addiction. The goal of this review is to summarize the current knowledge of Sigmar1 biology focusing the recent discoveries on Sigmar1’s molecular, cellular, pathophysiological, and biological functions.

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The Sigma-1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models

Cited by 30 publications

References 68 publications

Sigma-1 Receptor Is Critical for Mitochondrial Activity and Unfolded Protein Response in Larval Zebrafish

Sigma-1 Receptor Is Critical for Mitochondrial Activity and Unfolded Protein Response in Larval Zebrafish

Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

Sigmar1’s Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology

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