Neuroprotective Effect of σ1-Receptors on the Cell Model of Huntington’s Disease

Bolshakova, Anastasia; Kraskovskaya, Nina; Kukanova, E. O.; Власова, О. Л.; Bezprozvanny, Ilya

doi:10.1007/s10517-017-3968-7

Cited by 14 publications

(18 citation statements)

References 9 publications

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“…It has also been suggested that flux through the glycolytic enzyme GAPDH may be relevant ( 74 ), although the results presented here suggest that the major impairment by mutant HTT occurs after that step in glycolysis. Recent studies have also suggested a possible role of the connection between mitochondria and the endoplasmic reticulum, perhaps via sigma-1 receptors ( 75 , 76 ), agonists of which have been shown to be protective in HD models ( 77 , 78 ). Pyruvate can rescue impaired ATP production caused by sigma-1 mutations ( 79 ).…”

Section: Discussionmentioning

confidence: 99%

Bioenergetic deficits in Huntington’s disease iPSC-derived neural cells and rescue with glycolytic metabolites

Kedaigle

Fraenkel

Atwal

et al. 2019

Human Molecular Genetics

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Altered cellular metabolism is believed to be an important contributor to pathogenesis of the neurodegenerative disorder Huntington’s disease (HD). Research has primarily focused on mitochondrial toxicity, which can cause death of the vulnerable striatal neurons, but other aspects of metabolism have also been implicated. Most previous studies have been carried out using postmortem human brain or non-human cells. Here, we studied bioenergetics in an induced pluripotent stem cell-based model of the disease. We found decreased adenosine triphosphate (ATP) levels in HD cells compared to controls across differentiation stages and protocols. Proteomics data and multiomics network analysis revealed normal or increased levels of mitochondrial messages and proteins, but lowered expression of glycolytic enzymes. Metabolic experiments showed decreased spare glycolytic capacity in HD neurons, while maximal and spare respiratory capacities driven by oxidative phosphorylation were largely unchanged. ATP levels in HD neurons could be rescued with addition of pyruvate or late glycolytic metabolites, but not earlier glycolytic metabolites, suggesting a role for glycolytic deficits as part of the metabolic disturbance in HD neurons. Pyruvate or other related metabolic supplements could have therapeutic benefit in HD.

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Section: Discussionmentioning

confidence: 99%

Bioenergetic deficits in Huntington’s disease iPSC-derived neural cells and rescue with glycolytic metabolites

Kedaigle

Fraenkel

Atwal

et al. 2019

Human Molecular Genetics

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“…Many S1R agonists are anti-amnestic, synaptogenetic, and neuroprotective in conditions of neuronal stress (Antonini et al, 2009; Hindmarch and Hashimoto, 2010; Ruscher et al, 2011; Bolshakova et al, 2016). They also mitigate disease and symptoms in experimental models of ALS (Mancuso et al, 2012; Ono et al, 2014; Peviani et al, 2014; Ionescu et al, 2019), Alzheimer’s disease (AD) (Meunier and Hayashi, 2010; Fisher et al, 2016; Maurice and Goguadze, 2017; Hall et al, 2018; Goguadze et al, 2019; Ryskamp et al, 2019), Parkinson’s disease (PD) (Francardo et al, 2014; Francardo et al, 2019) Huntington’s disease (HD) (Squitieri et al, 2015; Geva et al, 2016; Bol’shakova et al, 2017; Garcia-Miralles et al, 2017; Ryskamp et al, 2017; Kusko et al, 2018) stroke (Allahtavakoli and Jarrott, 2011; Ruscher et al, 2011, 2012; Sato et al, 2014; Urfer et al, 2014) and traumatic brain injury (Dong et al, 2016). By contrast, S1R deficiency exacerbates progression of neurological disorders (Mavlyutov et al, 2011, 2013; Ha et al, 2012; Francardo et al, 2014; Miki et al, 2015; Maurice et al, 2018) as well as symptoms commonly associated with neurodegenerative diseases.…”

Section: S1r As a Target For Treating Neurodegenerative Diseasesmentioning

confidence: 99%

Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases

et al. 2019

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Sigma-1 receptor (S1R) is a multi-functional, ligand-operated protein situated in endoplasmic reticulum (ER) membranes and changes in its function and/or expression have been associated with various neurological disorders including amyotrophic lateral sclerosis/frontotemporal dementia, Alzheimer’s (AD) and Huntington’s diseases (HD). S1R agonists are broadly neuroprotective and this is achieved through a diversity of S1R-mediated signaling functions that are generally pro-survival and anti-apoptotic; yet, relatively little is known regarding the exact mechanisms of receptor functioning at the molecular level. This review summarizes therapeutically relevant mechanisms by which S1R modulates neurophysiology and implements neuroprotective functions in neurodegenerative diseases. These mechanisms are diverse due to the fact that S1R can bind to and modulate a large range of client proteins, including many ion channels in both ER and plasma membranes. We summarize the effect of S1R on its interaction partners and consider some of the cell type- and disease-specific aspects of these actions. Besides direct protein interactions in the endoplasmic reticulum, S1R is likely to function at the cellular/interorganellar level by altering the activity of several plasmalemmal ion channels through control of trafficking, which may help to reduce excitotoxicity. Moreover, S1R is situated in lipid rafts where it binds cholesterol and regulates lipid and protein trafficking and calcium flux at the mitochondrial-associated membrane (MAM) domain. This may have important implications for MAM stability and function in neurodegenerative diseases as well as cellular bioenergetics. We also summarize the structural and biochemical features of S1R proposed to underlie its activity. In conclusion, S1R is incredibly versatile in its ability to foster neuronal homeostasis in the context of several neurodegenerative disorders.

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“…S1R agonists are procognitive, synaptogenetic and neuroprotective in conditions of neuronal stress (Antonini et al, 2009;Bolshakova et al, 2016;Hindmarch and Hashimoto, 2010;Ruscher et al, 2011) and as a result they are beneficial in experimental models of Huntington's disease (HD) (Bol'shakova et al, 2017;Ryskamp et al, 2017;Squitieri et al, 2015) (Garcia-Miralles et al, 2017Geva et al, 2016;Kusko et al, 2018), Parkinson's disease (Francardo et al, 2014) and AD (Fisher et al, 2016;Hall et al, 2017;Maurice and Goguadze, 2017;Meunier et al, 2006). For example, we discovered that the mixed muscarinic/S1R agonist AF710B prevents the loss of mushroom spines in hippocampal cultures prepared from APP-KI or PS1-KI mice (Fisher et al, 2016).…”

Section: S1r As a Target For Pridopidine In Admentioning

confidence: 99%

Pridopidine stabilizes mushroom spines in mouse models of Alzheimer's disease by acting on the sigma-1 receptor

Ryskamp

et al. 2019

Neurobiology of Disease

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There is evidence that cognitive decline in Alzheimer's disease (AD) results from deficiencies in synaptic communication (e.g., loss of mushroom-shaped 'memory spines') and neurodegenerative processes. This might be treated with sigma-1 receptor (S1R) agonists, which are broadly neuroprotective and modulate synaptic plasticity. For example, we previously found that the mixed muscarinic/S1R agonist AF710B prevents mushroom spine loss in hippocampal cultures from APP knock-in (APP-KI) and presenilin-1-M146V knock-in (PS1-KI) mice. We also found that the "dopaminergic stabilizer" pridopidine (structurally similar to the S1R agonist R(+)-3-PPP), is a high-affinity S1R agonist and is synaptoprotective in a mouse model of Huntington disease. Here we tested whether pridopidine and R(+)-3-PPP are synaptoprotective in models of AD and whether this requires S1R. We also examined the effects of pridopidine on long-term potentiation (LTP), endoplasmic reticulum calcium and neuronal store-operated calcium entry (nSOC) in spines, both of which are dysregulated in AD, contributing to synaptic pathology. We report here that pridopidine and 3-PPP protect mushroom spines from Aβ 42 oligomer toxicity in primary WT *

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Neuroprotective Effect of σ1-Receptors on the Cell Model of Huntington’s Disease

Cited by 14 publications

References 9 publications

Bioenergetic deficits in Huntington’s disease iPSC-derived neural cells and rescue with glycolytic metabolites

Bioenergetic deficits in Huntington’s disease iPSC-derived neural cells and rescue with glycolytic metabolites

Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases

Pridopidine stabilizes mushroom spines in mouse models of Alzheimer's disease by acting on the sigma-1 receptor

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