Sigma Receptor Type 1 Gene Variation in a Group of Polish Patients with Alzheimer’s Disease and Mild Cognitive Impairment

Maruszak, Aleksandra; Safranow, Krzysztof; Gacia, Magdalena; Gabryelewicz, Tomasz; Słowik, Agnieszka; Styczyńska, Maria; Pepłońska, Beata; Golan, Maciej P.; Żekanowski, Cezary; Barcikowska, Maria

doi:10.1159/000101990

Cited by 30 publications

(20 citation statements)

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“…Data from [60], [122], [142], and [46], respectively. sigma-1 receptor allele, genotype, haplotype, and diplotype distributions were observed between the studied groups [73].…”

Section: Changes Of Sigma Receptor Density In Aging and Neurodegeneramentioning

confidence: 88%

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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“…Data from [60], [122], [142], and [46], respectively. sigma-1 receptor allele, genotype, haplotype, and diplotype distributions were observed between the studied groups [73].…”

Section: Changes Of Sigma Receptor Density In Aging and Neurodegeneramentioning

confidence: 88%

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: 97%

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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“…The polymorphism c.5A>C (rs1800866, resulting in an amino acid substitution Q2P) in the first exon is in complete linkage disequilibrium with certain polymorphisms in the promoter, and the haplotype TT-241-240P2 shows a 43% reduction in SIGMAR1 transcription activity compared to its pair GC-241-240Q2 [18]. This functional polymorphism has been associated with AD risk in two different populations with different results [14,19]. In Japanese the SIGMAR1-5C allele may have a protective role against AD susceptibility [14], but in Polish it appears to slightly increase AD risk in APOE 4 allele carriers [19].…”

Section: Introductionmentioning

confidence: 99%

Genetic Polymorphisms in Sigma-1 Receptor and Apolipoprotein E Interact to Influence the Severity of Alzheimers Disease

Huang

Zheng²,

Halliday³

et al. 2011

CAR

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Apolipoprotein E (APOE) ε4 allele and sigma-1 receptor (SIGMAR1) c.5C (Q2P) polymorphisms have been acknowledged as risk factors for developing Alzheimer's disease (AD). However, whether these polymorphisms influence the disease process is unclear. Therefore, two cohorts with a clinical diagnosis of AD were recruited, a postmortem confirmed Australian cohort (82 cases) from the Australian Brain Bank Network, and a Chinese cohort with detailed clinical assessments recruited through an epidemiology study in Shanghai and through the neurology department outpatients clinic of Shanghai Ruijin Hospital (330 cases). SIGMAR1 Q2P and APOE genotyping was performed on all cases. Dementia severity in the Chinese cohort was assessed using MMSE scores, and the stages of senile plaques and neurofibrillary tangles (NFT) assessed in the Australian cohort. Associations between SIGMAR1 Q2P and APOE genotypes and disease severity were assessed using SPSS. Results confirmed that APOE 4 allele associated with increased NFT stages and cognitive decline, with carriers with one APOE ε2 or ε3 allele often having better clinical outcomes compared to carriers with none or two ε2 or ε3 alleles respectively. SIGMAR1 c.5C polymorphism alone did not associate with MMSE score variability in Chinese or with pathological stages in Caucasians. However, the association studies revealed a significant genetic interaction between the APOE ε4 allele and SIGMAR1 2P carriers in both populations, i.e., in APOE non ε4 allele carriers, SIGMAR1 2P variant had increased cognitive dysfunction and more advanced stages of NFT. Our data demonstrate that SIGMAR1 and APOE interact to influence AD severity across ethnic populations.

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Sigma Receptor Type 1 Gene Variation in a Group of Polish Patients with Alzheimer’s Disease and Mild Cognitive Impairment

Cited by 30 publications

References 51 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

Genetic Polymorphisms in Sigma-1 Receptor and Apolipoprotein E Interact to Influence the Severity of Alzheimers Disease

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