scholarly journals Increased expression of AT-1/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation

2016 ◽  
Vol 213 (7) ◽  
pp. 1267-1284 ◽  
Author(s):  
Rikki Hullinger ◽  
Mi Li ◽  
Jingxin Wang ◽  
Yajing Peng ◽  
James A. Dowell ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Secretory Pathway ◽  
Premature Death ◽  
Autism Spectrum ◽  
Lysine Acetylation ◽  
Acetyl Coa ◽  
Dendritic Branching ◽  
Familial Spastic Paraplegia ◽  
Epigenetic Modulation ◽  
Mitochondrial Adaptation

The import of acetyl-CoA into the lumen of the endoplasmic reticulum (ER) by AT-1/SLC33A1 regulates Nε-lysine acetylation of ER-resident and -transiting proteins. Specifically, lysine acetylation within the ER appears to influence the efficiency of the secretory pathway by affecting ER-mediated quality control. Mutations or duplications in AT-1/SLC33A1 have been linked to diseases such as familial spastic paraplegia, developmental delay with premature death, and autism spectrum disorder with intellectual disability. In this study, we generated an AT-1 Tg mouse model that selectively overexpresses human AT-1 in neurons. These animals demonstrate cognitive deficits, autistic-like social behavior, aberrations in synaptic plasticity, an increased number of dendritic spines and branches, and widespread proteomic changes. We also found that AT-1 activity regulates acetyl-CoA flux, causing epigenetic modulation of the histone epitope H3K27 and mitochondrial adaptation. In conclusion, our results indicate that increased expression of AT-1 can cause an autistic-like phenotype by affecting key neuronal metabolic pathways.

scholarly journals Acetyl-CoA flux from the cytosol to the ER regulates engagement and quality of the secretory pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Inca A. Dieterich ◽  
Yusi Cui ◽  
Megan M. Braun ◽  
Alexis J. Lawton ◽  
Nicklaus H. Robinson ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Secretory Pathway ◽  
Severe Disease ◽  
Lysine Acetylation ◽  
Acetyl Coa ◽  
Disease Phenotypes ◽  
Membrane Protein Trafficking ◽  
Duplication Events ◽  
Glycan Modification

AbstractNε-lysine acetylation in the ER is an essential component of the quality control machinery. ER acetylation is ensured by a membrane transporter, AT-1/SLC33A1, which translocates cytosolic acetyl-CoA into the ER lumen, and two acetyltransferases, ATase1 and ATase2, which acetylate nascent polypeptides within the ER lumen. Dysfunctional AT-1, as caused by gene mutation or duplication events, results in severe disease phenotypes. Here, we used two models of AT-1 dysregulation to investigate dynamics of the secretory pathway: AT-1 sTg, a model of systemic AT-1 overexpression, and AT-1S113R/+, a model of AT-1 haploinsufficiency. The animals displayed reorganization of the ER, ERGIC, and Golgi apparatus. In particular, AT-1 sTg animals displayed a marked delay in Golgi-to-plasma membrane protein trafficking, significant alterations in Golgi-based N-glycan modification, and a marked expansion of the lysosomal network. Collectively our results indicate that AT-1 is essential to maintain proper organization and engagement of the secretory pathway.

scholarly journals Endoplasmic reticulum acetyltransferases Atase1 and Atase2 differentially regulate reticulophagy, macroautophagy and cellular acetyl-CoA metabolism

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Michael J. Rigby ◽  
Alexis J. Lawton ◽  
Gulpreet Kaur ◽  
Varuna C. Banduseela ◽  
William E. Kamm ◽  
...  
Keyword(s):  
Quality Control ◽  
Secretory Pathway ◽  
Control Mechanism ◽  
Cellular Biology ◽  
Lysine Acetylation ◽  
Type Ii ◽  
Acetyl Coa ◽  
Toxic Protein ◽  
Quality Control Mechanism

AbstractNε-lysine acetylation in the ER lumen is a recently discovered quality control mechanism that ensures proteostasis within the secretory pathway. The acetyltransferase reaction is carried out by two type-II membrane proteins, ATase1/NAT8B and ATase2/NAT8. Prior studies have shown that reducing ER acetylation can induce reticulophagy, increase ER turnover, and alleviate proteotoxic states. Here, we report the generation of Atase1−/− and Atase2−/− mice and show that these two ER-based acetyltransferases play different roles in the regulation of reticulophagy and macroautophagy. Importantly, knockout of Atase1 alone results in activation of reticulophagy and rescue of the proteotoxic state associated with Alzheimer’s disease. Furthermore, loss of Atase1 or Atase2 results in widespread adaptive changes in the cell acetylome and acetyl-CoA metabolism. Overall, our study supports a divergent role of Atase1 and Atase2 in cellular biology, emphasizing ATase1 as a valid translational target for diseases characterized by toxic protein aggregation in the secretory pathway.

Sirtuin-dependent reversible lysine acetylation controls the activity of acetyl-Coenzyme A synthetase in Campylobacter jejuni

2021 ◽  
Author(s):  
Victoria L. Jeter ◽  
Jorge C. Escalante-Semerena
Keyword(s):  
Campylobacter Jejuni ◽  
Posttranslational Modifications ◽  
Active Site ◽  
Protein Function ◽  
Metabolic Enzyme ◽  
Lysine Acetylation ◽  
Class Iii ◽  
Acetyl Coa

Posttranslational modifications are mechanisms for rapid control of protein function used by cells from all domains of life. Acetylation of the epsilon amino group ( N ε ) of an active-site lysine of the AMP-forming acetyl-CoA synthetase (Acs) enzyme is the paradigm for the posttranslational control of the activity of metabolic enzymes. In bacteria, the alluded active-site lysine of Acs enzymes can be modified by a number of different GCN5-type N -acetyltransferases (GNATs). Acs activity is lost as a result of acetylation, and restored by deacetylation. Using a heterologous host, we show that Campylobacter jejuni NCTC11168 synthesizes enzymes that control Acs function by reversible lysine acetylation (RLA). This work validates the function of gene products encoded by the cj1537c , cj1715, and cj1050c loci, namely the AMP-forming acetate:CoA ligase ( Cj Acs), a type IV GCN5-type lysine acetyltransferase (GNAT, hereafter Cj LatA), and a NAD + -dependent (class III) sirtuin deacylase ( Cj CobB), respectively. To our knowledge, these are the first in vivo and in vitro data on C. jejuni enzymes that control the activity of Cj Acs. IMPORTANCE This work is important because it provides the experimental evidence needed to support the assignment of function to three key enzymes, two of which control the reversible posttranslational modification of an active-site lysyl residue of the central metabolic enzyme acetyl-CoA synthetase ( Cj Acs). We can now generate Campylobacter jejuni mutant strains defective in these functions, so we can establish the conditions in which this mode of regulation of Cj Acs is triggered in this bacterium. Such knowledge may provide new therapeutic strategies for the control of this pathogen.

scholarly journals Comment on ‘YcgC represents a new protein deacetylase family in prokaryotes’

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Magdalena Kremer ◽  
Nora Kuhlmann ◽  
Marius Lechner ◽  
Linda Baldus ◽  
Michael Lammers
Keyword(s):  
Lysine Acetylation ◽  
Post Translational Modification ◽  
Donor Molecule ◽  
Acetyl Coa ◽  
Lysine Deacetylases ◽  
Protein Deacetylase ◽  
New Protein

Lysine acetylation is a post-translational modification that is conserved from bacteria to humans. It is catalysed by the activities of lysine acetyltransferases, which use acetyl-CoA as the acetyl-donor molecule, and lysine deacetylases, which remove the acetyl moiety. Recently, it was reported that YcgC represents a new prokaryotic deacetylase family with no apparent homologies to existing deacetylases (Tu et al., 2015). Here we report the results of experiments which demonstrate that YcgC is not a deacetylase.

Online education of students with mild intellectual disability and autism spectrum disorder during the COVID-19 pandemic in the opinion of teacher

2021 ◽  
Vol LXXXII (5) ◽  
pp. 334-346
Author(s):  
Marzena Buchnat ◽  
Aneta Wojciechowska
Keyword(s):  
Intellectual Disability ◽  
Online Education ◽  
Children And Adolescents ◽  
Cognitive Deficits ◽  
Autism Spectrum ◽  
Mild Intellectual Disability ◽  
Online Questionnaire ◽  
Difficult Situation ◽  
New Material ◽  
Education Of Students

Online education, introduced obligatorily during the COVID-19 pandemic, poses a great challenge for teachers, students and their parents. Children and adolescents with mild intellectual disability or with ASD, that due to their cognitive deficits need appropriate support, are in a particular difficult situation. The aim of the conducted research was to specify the possible problems of online education of students with mild intellectual disability and ASD in their teachers' opinion. The research consisted in answering the questions from an online questionnaire. 114 teachers teaching children and adolescents with mild intellectual disability and 114 teachers teaching children and adolescents with ASD participated in the research. The results show that according to the teachers the biggest problems of students with mild intellectual disability and ASD are: understanding and remembering new material, lack of contact with their peers. Students with ASD are characterized by significantly greater intensity of the occurrence of difficulties in the area of education than people with mild intellectual disability. Difficulties in both groups of examined children and adolescents oblige to appropriately support them in online education and cooperation with their parents.

scholarly journals Advantages of the multiple case series approach to the study of cognitive deficits in autism spectrum disorder

2009 ◽  
Vol 47 (13) ◽  
pp. 2981-2988 ◽  
Author(s):  
Karren J. Towgood ◽  
Julia D.I. Meuwese ◽  
Sam J. Gilbert ◽  
Martha S. Turner ◽  
Paul W. Burgess
Keyword(s):  
Autism Spectrum Disorder ◽  
Cognitive Deficits ◽  
Case Series ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Multiple Case

scholarly journals Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder

2021 ◽  
Vol 7 (1) ◽  
pp. e551
Author(s):  
Jennifer M. Bain ◽  
Olivia Thornburg ◽  
Cheryl Pan ◽  
Donnielle Rome-Martin ◽  
Lia Boyle ◽  
...  
Keyword(s):  
Language Impairment ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Retrospective Chart Review ◽  
Premature Death ◽  
Parent Report ◽  
Autism Spectrum ◽  
Pathogenic Variants ◽  
Motor Problems ◽  
Cortical Visual Impairment

ObjectiveTo expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals.MethodsParticipants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures.ResultsWe expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2–38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition.ConclusionsThe spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.

scholarly journals Early EEG and behavioral alterations in Dravet mice

2020 ◽  
Author(s):  
Saja Fadila ◽  
Shir Quinn ◽  
Ana Turchetti Maia ◽  
Daniel Yakubovich ◽  
Karen L. Anderson ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Cognitive Deficits ◽  
Normal Development ◽  
Premature Death ◽  
Dravet Syndrome ◽  
Disease Stage ◽  
Total Power ◽  
List Type ◽  
Eeg Power ◽  
Background Eeg

AbstractDravet Syndrome (Dravet) is a severe childhood epileptic encephalopathy. The disease begins around the age of six months, with a febrile stage, characterized by febrile seizures with otherwise normal development. By the end of the first year of life, the disease progresses to the worsening stage, featuring recurrent intractable seizures and the appearance of additional comorbidities, including global developmental delay, cognitive deficits, hyperactivity and motor problems. Later, in early school years, Dravet reaches the stabilization stage, in which seizure burden decreases, while Dravet-associated comorbidities persist. Dravet syndrome mouse models (DS) faithfully recapitulate the three stages of the human syndrome. Here, we performed power spectral analyses of background EEG activity in DS and their wild-type (WT) littermates, demonstrating disease stage-related alterations. Specifically, while the febrile stage activity resembled that of WT mice, we observed a marked reduction in total power during the worsening stage and a smaller reduction during the stabilization stage. Moreover, low EEG power at the worsening stage correlated with increased risk for premature death, suggesting that such measurements can potentially be used as a marker for Dravet severity. With normal development at the febrile stage and the presentation of developmental delay at the worsening stage, the contribution of recurrent seizures to the emergence of Dravet-associated comorbidities is still debated. Thus, we further characterized the behavior of WT and DS mice during the different stages of Dravet. At the febrile stage, despite their normal background EEG patterns, DS mice already demonstrated motor impairment and hyperactivity in the open field, that persisted to the worsening and stabilization stages. Conversely, clear evidence for deficits in working memory emerged later in life, during the worsening stage. These results indicate that despite the mild epilepsy at the febrile stage, DS development is already altered, suggesting that the pathophysiological mechanisms governing the appearance of some Dravet behavioral comorbidities may be independent of the epileptic phenotype.HighlightsReduction in background EEG power in DravetLow EEG power correlates with the risk of premature deathMotor deficits and hyperactivity are evident as early as the febrile stageCognitive deficits and detection of increased anxiety begin at the worsening stage

scholarly journals Neurofeedback Training for Social Cognitive Deficits: A Systematic Review

2020 ◽  
Vol 16 (10) ◽  
pp. 151
Author(s):  
Manju Kumari ◽  
Ankita Sharma
Keyword(s):  
Systematic Review ◽  
Social Cognition ◽  
Cognitive Deficits ◽  
Neural Activity ◽  
Social Cognitive ◽  
Autism Spectrum ◽  
Present Review ◽  
Neurofeedback Training ◽  
Treatment Variable ◽  
Social Cognitive Deficits

<p><strong>Orndorff and his colleagues [1]</strong> suggested that if a neural activity is considered a treatment variable instead of outcome, it widens the scope of research and has a specific implication for social neuroscience. Given this, the empirical evidence is collected and analyzed where neural activity as self-manipulation design through neurofeedback training specifically for social cognition deficit is done. The objective of the present article is to provide a systematic review of 1) how NFT is utilized to treat social cognitive deficits, 2) how NFT is utilized to target Social Cognition Deficit in ASD, 3) examining the directions, strengths, and quality of evidence to support the use of NFT for ASD. The databases for studies were searched in PubMed, MEDLINE, EMBASE, Springer, Science Direct, Psychinfo, and Google Scholar, using combinations of the following keywords: ‘Neurofeedback,’ ‘Autism Spectrum Disorder,’ ‘Mu Rhythm’ and ‘Social Cognition.’ Studies were eligible for inclusion if they were specific to 1) autistic and typically developed population, 2) intervention study, 3) Delivered by NFT, 4) participants showed social cognitive deficit and/or improvement. Total one eighty-seven studies were found of key interest; out of which 17 studies were eligible for inclusion in this review. All studies reported the improvement in different domains of social cognition and were moderately methodologically sound. Eleven out of seventeen studies satisfied the trainability and interpretability criteria suggested by <strong>Zoefel and his colleagues [2].</strong> The conclusion from the present review is in line with comments of <strong>Marzbani and colleagues [3]</strong> that, ‘current research does not provide sufficient conclusive results about its efficacy.’ The patterns and directions concluded from studies related to protocol, methodology and results are discussed in detail in the present review.</p>

Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders

2019 ◽  
Vol 70 (1) ◽  
pp. 167-181 ◽  
Author(s):  
Ilse Gantois ◽  
Jelena Popic ◽  
Arkady Khoutorsky ◽  
Nahum Sonenberg
Keyword(s):  
Fragile X Syndrome ◽  
Cognitive Deficits ◽  
Neurological Disorders ◽  
Fragile X ◽  
Autism Spectrum ◽  
Cellular Models ◽  
The Us ◽  
Mental Retardation Protein ◽  
Drug Treatments ◽  
Core Symptoms

Fragile X syndrome (FXS) is the most frequent inherited form of intellectual disability and autism spectrum disorder. Loss of the fragile X mental retardation protein, FMRP, engenders molecular, behavioral, and cognitive deficits in FXS patients. Experiments using different animal models advanced our knowledge of the pathophysiology of FXS and led to the discovery of many targets for drug treatments. In this review, we discuss the potential of metformin, an antidiabetic drug approved by the US Food and Drug Administration, to correct core symptoms of FXS and other neurological disorders in humans. We summarize its mechanisms of action in different animal and cellular models and human diseases.

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