Function of sigma1 receptors in Parkinson's disease

Mishina, Masayoshi; Ishiwata, Kiichi; Ishii, Kenji; Kitamura, Shin; Kimura, Yuichi; Kawamura, Kazunori; Oda, Kazuhiro; Sasaki, T.; Sakayori, Osamu; Hamamoto, Makoto; Kobayashi, Sohei; Katayama, Yasuo

doi:10.1111/j.1600-0404.2005.00432.x

Cited by 139 publications

(119 citation statements)

References 27 publications

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“…In a small group of patients with early Parkinson's disease (n = 6), the BP of 11 C-SA4503 was found to be significantly lower on the more affected than the less affected side of the anterior putamen, although there was no significant difference in BP between patients and controls [108]. These data suggest that Parkinson's disease may be associated with a loss of sigma-1 receptors from the putamen, although the decrease is less striking than that observed in the cerebral cortex in AD.…”

Section: Changes Of Sigma Receptor Density In Aging and Neurodegeneramentioning

confidence: 99%

The cholinergic system, sigma-1 receptors and cognition

Waarde

Ramakrishnan

Rybczynska

et al. 2011

Behavioural Brain Research

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a b s t r a c tThis article provides an overview of present knowledge regarding the relationship between the cholinergic system and sigma-1 receptors, and discusses potential applications of sigma-1 receptor agonists in the treatment of memory deficits and cognitive disorders. Sigma-1 receptors, initially considered as a subtype of the opioid family, are unique ligand-regulated molecular chaperones in the endoplasmatic reticulum playing a modulatory role in intracellular calcium signaling and in the activity of several neurotransmitter systems, particularly the cholinergic and glutamatergic pathways. Several central nervous system (CNS) drugs show high to moderate affinities for sigma-1 receptors, including acetylcholinesterase inhibitors (donepezil), antipsychotics (haloperidol, rimcazole), selective serotonin reuptake inhibitors (fluvoxamine, sertraline) and monoamine oxidase inhibitors (clorgyline). These compounds can influence cognitive functions both via their primary targets and by activating sigma-1 receptors in the CNS. Sigma-1 agonists show powerful anti-amnesic and neuroprotective effects in a large variety of animal models of cognitive dysfunction involving, among others (i) pharmacologic target blockade (with muscarinic or NMDA receptor antagonists or p-chloroamphetamine); (ii) selective lesioning of cholinergic neurons; (iii) CNS administration of ␤-amyloid peptides; (iv) aging-induced memory loss, both in normal and senescentaccelerated rodents; (v) neurodegeneration induced by toxic compounds (CO, trimethyltin, cocaine), and (vi) prenatal restraint stress.

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Section: Changes Of Sigma Receptor Density In Aging and Neurodegeneramentioning

confidence: 99%

The cholinergic system, sigma-1 receptors and cognition

Waarde

Ramakrishnan

Rybczynska

et al. 2011

Behavioural Brain Research

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“…Those results support the notion that Sig-1Rs, by interacting with endogenous myristic acid, play a pivotal role in the p35 myristoylation and degradation. Discussion Sig-1Rs have been reported to play a role in the pathogenesis of neurodegenerative disorders including AD (30,45,46), Parkinson's disease (47,48), and motor neuron disorders (49)(50)(51). The underlying molecular mechanisms of Sig-1R action remain to be totally clarified.…”

Section: Sig-1r Controls P35 Degradation Mainly Through the Proteasomalmentioning

confidence: 99%

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

Tsai

Pokrass

Klauer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t ½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t ½ , promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor's interaction with myristic acid. In Sig-1R-KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R-KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R-KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25.A xons are structurally and functionally distinct protrusions of neurons that modulate neurotransmitter release and neural function. Malfunction of axonal maintenance, regeneration, and target recognition contribute to CNS disorders such as Alzheimer's disease (AD), Parkinson's disease, stroke, and spinal cord injuries (1-3). Cyclin-dependent kinase (Cdk) 5 activities within the axon play a significant role in the cytoskeletal dynamics of microtubules and actin neurofilaments (NFs), which determine axonal path and length. Specifically, cdk5 active complexes phosphorylate proteins that contribute to the stabilization or destabilization of microtubules, formation of neurofibrillary tangles, and axonal pathfinding (4-6).Cdk5 is a ubiquitously expressed enzyme; however, its activator, p35, is almost exclusively expressed in neurons (7,8). Cdk5 signaling supports neurite projection and proper neuronal migration (9-11). Dysregulation of cdk5 activity leads to hyperphosphorylation of several substrates, including NF proteins and tau, which causes the formation of neurofibrillary tangles (6, 12). Although the kinetics of cdk5 activity when in complex with p35 or p25 are the same, cdk5/p25 complexes are proposed to be responsible for neurodegenerative pathophysiology because of their longer duration o...

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“…Several brain-related pathologies are characterized by a decrease in the density of s 1 Rs. A reduction of 26% in postmortem 3 H-1, 3 di-o-tolylguanidine (DTG) binding studies was detected in the hippocampus of Alzheimer's patients (3), and in vivo 11 C-SA4503 imaging studies demonstrated a reduction of at least 25% in the regions of interest in both Parkinson's and Alzheimer's patients (4,5). Also, s 1 Rs might be implicated in the mechanisms of action of selective serotonin reuptake inhibitors.…”

mentioning

confidence: 96%

Distinctive In Vivo Kinetics of the New σ₁ Receptor Ligands (R)-(+)- and (S)-(–)-¹⁸F-Fluspidine in Porcine Brain

et al. 2014

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Function of sigma1 receptors in Parkinson's disease

Abstract: Release of dopamine is reduced asymmetrically in the putamen of early PD. [11C]SA4503 PET is an indicator of presynaptic dopaminergic damage in PD.

Cited by 139 publications

References 27 publications

The cholinergic system, sigma-1 receptors and cognition

The cholinergic system, sigma-1 receptors and cognition

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

Distinctive In Vivo Kinetics of the New σ₁ Receptor Ligands (R)-(+)- and (S)-(–)-¹⁸F-Fluspidine in Porcine Brain

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Function of sigma1 receptors in Parkinson's disease

Abstract: Release of dopamine is reduced asymmetrically in the putamen of early PD. [11C]SA4503 PET is an indicator of presynaptic dopaminergic damage in PD.

Cited by 139 publications

References 27 publications

The cholinergic system, sigma-1 receptors and cognition

The cholinergic system, sigma-1 receptors and cognition

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

Distinctive In Vivo Kinetics of the New σ1 Receptor Ligands (R)-(+)- and (S)-(–)-18F-Fluspidine in Porcine Brain

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Distinctive In Vivo Kinetics of the New σ₁ Receptor Ligands (R)-(+)- and (S)-(–)-¹⁸F-Fluspidine in Porcine Brain