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1.
Mol Psychiatry ; 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38879719

RESUMO

Substance use disorders (SUD) and drug addiction are major threats to public health, impacting not only the millions of individuals struggling with SUD, but also surrounding families and communities. One of the seminal challenges in treating and studying addiction in human populations is the high prevalence of co-morbid conditions, including an increased risk of contracting a human immunodeficiency virus (HIV) infection. Of the ~15 million people who inject drugs globally, 17% are persons with HIV. Conversely, HIV is a risk factor for SUD because chronic pain syndromes, often encountered in persons with HIV, can lead to an increased use of opioid pain medications that in turn can increase the risk for opioid addiction. We hypothesize that SUD and HIV exert shared effects on brain cell types, including adaptations related to neuroplasticity, neurodegeneration, and neuroinflammation. Basic research is needed to refine our understanding of these affected cell types and adaptations. Studying the effects of SUD in the context of HIV at the single-cell level represents a compelling strategy to understand the reciprocal interactions among both conditions, made feasible by the availability of large, extensively-phenotyped human brain tissue collections that have been amassed by the Neuro-HIV research community. In addition, sophisticated animal models that have been developed for both conditions provide a means to precisely evaluate specific exposures and stages of disease. We propose that single-cell genomics is a uniquely powerful technology to characterize the effects of SUD and HIV in the brain, integrating data from human cohorts and animal models. We have formed the Single-Cell Opioid Responses in the Context of HIV (SCORCH) consortium to carry out this strategy.

2.
Proc Natl Acad Sci U S A ; 112(21): 6742-7, 2015 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-25964330

RESUMO

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 t½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t½, 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.


Assuntos
Axônios/metabolismo , Fosfotransferases/metabolismo , Receptores sigma/metabolismo , Proteínas tau/metabolismo , Animais , Axônios/ultraestrutura , Calpaína/metabolismo , Quinase 5 Dependente de Ciclina/metabolismo , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Ácido Mirístico/metabolismo , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Neurogênese/fisiologia , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Receptores sigma/deficiência , Receptores sigma/genética , Receptor Sigma-1
3.
Proc Natl Acad Sci U S A ; 112(47): E6562-70, 2015 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-26554014

RESUMO

The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.


Assuntos
Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Cocaína/farmacologia , Membrana Nuclear/metabolismo , Receptores sigma/metabolismo , Transcrição Gênica/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Montagem e Desmontagem da Cromatina/genética , Proteínas de Ligação a DNA/metabolismo , Técnicas de Silenciamento de Genes , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Lamina Tipo A/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Monoaminoxidase/genética , Membrana Nuclear/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos , Fator de Transcrição Sp3 , Síndrome de Abstinência a Substâncias , Receptor Sigma-1
4.
Biochem Biophys Res Commun ; 482(2): 282-288, 2017 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-27847319

RESUMO

Skeletal muscle insulin resistance is considered to be the primary defect involved in type 2 diabetes mellitus (T2DM). Despite transcriptome studies in limited T2DM human subjects suggesting an association of T2DM with impaired oxidative phosphorylation in muscle, its molecular pathogenesis remains largely unknown. To identify dysregulated genes and gene networks that are associated with T2DM in human skeletal muscle, we examined expression patterns of 56,318 transcribed genes on 92 T2DM cases and 184 gender-, age- and race-matched non-diabetic controls from the Genotype-Tissue Expression (GTEx) database. RNA-Sequencing data suggest that diabetic skeletal muscle is characterized by decreased expression of genes that are related to insulin resistance (IRS2, MTOR, SLC2A4, and PPARA), carbohydrate, energy, and amino acid metabolism pathways (NDUFS1, NDUFA10, NDUFB4, NDUFB5, NDUFA5, NDUFB10, SDHB, SDHC, ATP5H, ATP5A, and ATP5J). Up-regulated genes in T2DM are mainly enriched in apoptosis pathways (TP53, GADD45A, TNFRSF10B, TP53AIP1, and PMAIP1), and notably include immune-related pathways suggestive of a response to various infectious diseases (C2, CFB, C4A, C4B, C1S, C1R, C3, HLA-DRA, HLA-DMA, HLA-DOA, and HLA-DPB1). These results confirm the essential regulation of impaired insulin signaling and oxidative phosphorylation in the muscle of T2DM patients, and provide novel molecular insights into the pathophysiological mechanisms of T2DM.


Assuntos
Apoptose/imunologia , Diabetes Mellitus Tipo 2/imunologia , Resistência à Insulina/imunologia , Proteínas Musculares/imunologia , Músculo Esquelético/imunologia , Transcriptoma/imunologia , Humanos , Infecções/imunologia , Transdução de Sinais/imunologia
5.
Oxid Med Cell Longev ; 2017: 4582135, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28883901

RESUMO

Sigma-1 receptor (Sig-1R) functions as a chaperon that interacts with multiple proteins and lipids and is implicated in neurodegenerative and psychiatric diseases. Here, we used Sig-1R KO mice to examine brain expression profiles of astrocytes and ubiquitinated proteins, which are both hallmarks of central nervous system (CNS) pathologies. Our results showed that Sig-1R KO induces increased glial fibrillary acidic protein (GFAP) expression in primary neuron-glia cultures and in the whole brain of fetus mice with concomitantly increased accumulations of ubiquitinated proteins. Astrogliosis was also observed in the neuron-glia culture. Upon proteasome or autophagy inhibitor treatments, the pronounced ubiquitinated proteins were further increased in Sig-1R KO neurons, indicating that the Sig-1R regulates both protein degradation and quality control systems. We found that Nrf2 (nuclear factor erythroid 2-related factor 2), which functions to overcome the stress condition, was enhanced in the Sig-1R KO systems especially when cells were under stressful conditions. Mutation or deficiency of Sig-1Rs has been observed in neurodegenerative models. Our study identifies the critical roles of Sig-1R in CNS homeostasis and supports the idea that functional complementation pathways are triggered in the Sig-1R KO pathology.


Assuntos
Gliose/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Receptores sigma/metabolismo , Animais , Antioxidantes/metabolismo , Western Blotting , Células Cultivadas , Sistema Nervoso Central/metabolismo , Imunofluorescência , Proteína Glial Fibrilar Ácida/metabolismo , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/fisiologia , Receptor Sigma-1
6.
Cell Rep ; 10(4): 616-32, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25640183

RESUMO

Human pluripotent stem cell (hPSC) lines exhibit repeated patterns of genetic variation, which can alter in vitro properties as well as suitability for clinical use. We examined associations between copy-number variations (CNVs) on chromosome 17 and hPSC mesodiencephalic dopaminergic (mDA) differentiation. Among 24 hPSC lines, two karyotypically normal lines, BG03 and CT3, and BG01V2, with trisomy 17, exhibited amplification of the WNT3/WNT9B region and rapid mDA differentiation. In hPSC lines with amplified WNT3/WNT9B, basic fibroblast growth factor (bFGF) signaling through mitogen-activated protein kinase (MAPK)/ERK amplifies canonical WNT signaling by phosphorylating LRP6, resulting in enhanced undifferentiated proliferation. When bFGF is absent, noncanonical WNT signaling becomes dominant due to upregulation of SIAH2, enhancing JNK signaling and promoting loss of pluripotency. When bFGF is present during mDA differentiation, stabilization of canonical WNT signaling causes upregulation of LMX1A and mDA induction. Therefore, CNVs in 17q21.31, a "hot spot" for genetic variation, have multiple and complex effects on hPSC cellular phenotype.


Assuntos
Neurônios/citologia , Neurônios/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Proteínas Wnt/metabolismo , Proteína Wnt3/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Linhagem Celular , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Proteínas Wnt/genética , Proteína Wnt3/genética
7.
Expert Opin Ther Targets ; 18(12): 1461-76, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25331742

RESUMO

INTRODUCTION: Sigma-1 receptors (Sig-1Rs) are molecular chaperones that reside mainly in the endoplasmic reticulum (ER) but exist also in the proximity of the plasma membrane. Sig-1Rs are highly expressed in the CNS and are involved in many cellular processes including cell differentiation, neuritogenesis, microglia activation, protein quality control, calcium-mediated ER stress and ion channel modulation. Disturbance in any of the above cellular processes can accelerate the progression of many neurological disorders; therefore, the Sig-1R has been implicated in several neurological diseases. AREAS COVERED: This review broadly covers the functions of Sig-1Rs including several neurodegenerative disorders in humans and drug addiction-associated neurological disturbance in the case of HIV infection. We discuss how several Sig-1R ligands could be utilized in therapeutic approaches to treat those disorders. EXPERT OPINION: Emerging understanding of the cellular functions of this unique transmembrane chaperone may lead to the use of new agents or broaden the use of certain available ligands as therapeutic targets in those neurological disorders.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Transtornos Mentais/metabolismo , Chaperonas Moleculares/biossíntese , Doenças Neurodegenerativas/metabolismo , Receptores sigma/biossíntese , Animais , Humanos , Transtornos Mentais/tratamento farmacológico , Chaperonas Moleculares/antagonistas & inibidores , Antagonistas de Entorpecentes/administração & dosagem , Doenças Neurodegenerativas/tratamento farmacológico , Receptores sigma/antagonistas & inibidores , Receptor Sigma-1
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