Frameshift mutation of Timm8a1 gene in mouse leads to an abnormal mitochondrial structure in the brain, correlating with hearing and memory impairment

2020 ◽  
pp. jmedgenet-2020-106925
Author(s):  
Pingping Song ◽  
Yuqing Guan ◽  
Xia Chen ◽  
Chaochen Wu ◽  
An Qiao ◽  
...  
Keyword(s):  
Memory Impairment ◽  
Manganese Superoxide Dismutase ◽  
Frameshift Mutation ◽  
Intermembrane Space ◽  
Loss Of Function ◽  
Electron Microscopic ◽  
Causative Gene ◽  
Western Blot Assay ◽  
Mitochondrial Structure ◽  
The Brain

BackgroundDeafness-dystonia-optic neuronopathy (DDON) syndrome is a progressive X-linked recessive disorder characterised by deafness, dystonia, ataxia and reduced visual acuity. The causative gene deafness/dystonia protein 1 (DDP1)/translocase of the inner membrane 8A (TIMM8A) encodes a mitochondrial intermembrane space chaperon. The molecular mechanism of DDON remains unclear, and detailed information on animal models has not been reported yet.Methods and resultsWe characterized a family with DDON syndrome, in which the affected members carried a novel hemizygous variation in the DDP1 gene (NM_004085.3, c.82C>T, p.Q28X). We then generated a mouse line with the hemizygous mutation (p.I23fs49X) in the Timm8a1 gene using the clustered regularly interspaced short palindromic repeats /Cas9 technology. The deficient DDP1 protein was confirmed by western blot assay. Electron microscopic analysis of brain samples from the mutant mice indicated abnormal mitochondrial structure in several brain areas. However, Timm8a1I23fs49X/y mutation did not affect the import of mitochondria inner member protein Tim23 and outer member protein Tom40 as well as the biogenesis of the proteins in the mitochondrial oxidative phosphorylation system and the manganese superoxide dismutase (MnSOD / SOD-2). The male mice with Timm8a1I23fs49X/y mutant exhibited less weight gain, hearing impairment and cognitive deficit.ConclusionOur study suggests that frameshift mutation of the Timm8a1 gene in mice leads to an abnormal mitochondrial structure in the brain, correlating with hearing and memory impairment. Taken together, we have successfully generated a mouse model bearing loss-of-function mutation in Timm8a1.

scholarly journals Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations

2021 ◽  
Author(s):  
Niklas Schwarz ◽  
Simone Seiffert ◽  
Manuela Pendziwiat ◽  
Annika Rademacher ◽  
Tobias Bruenger ◽  
...  
Keyword(s):  
Functional Analysis ◽  
De Novo ◽  
Critical Role ◽  
Specific Response ◽  
Loss Of Function ◽  
Causative Gene ◽  
Characteristic Functional ◽  
Research Collaborations ◽  
The Brain

Background KCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (KV3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. Methods Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes. Results We identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid. Conclusion These findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of KV3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.

Metallic prions

2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown
Keyword(s):  
Prion Protein ◽  
Binding Capacity ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Published Data ◽  
Normal Brain ◽  
Copper Binding ◽  
Loss Of Function ◽  
Spongiform Encephalopathies ◽  
The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

scholarly journals Brain mast cells link the immune system to anxiety-like behavior

2008 ◽  
Vol 105 (46) ◽  
pp. 18053-18057 ◽  
Author(s):  
Katherine M. Nautiyal ◽  
Ana C. Ribeiro ◽  
Donald W. Pfaff ◽  
Rae Silver
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Neural Systems ◽  
Loss Of Function ◽  
Littermate Control ◽  
Cytokines And Chemokines ◽  
Function Models ◽  
The Brain

Mast cells are resident in the brain and contain numerous mediators, including neurotransmitters, cytokines, and chemokines, that are released in response to a variety of natural and pharmacological triggers. The number of mast cells in the brain fluctuates with stress and various behavioral and endocrine states. These properties suggest that mast cells are poised to influence neural systems underlying behavior. Using genetic and pharmacological loss-of-function models we performed a behavioral screen for arousal responses including emotionality, locomotor, and sensory components. We found that mast cell deficient KitW−sh/W−sh (sash−/−) mice had a greater anxiety-like phenotype than WT and heterozygote littermate control animals in the open field arena and elevated plus maze. Second, we show that blockade of brain, but not peripheral, mast cell activation increased anxiety-like behavior. Taken together, the data implicate brain mast cells in the modulation of anxiety-like behavior and provide evidence for the behavioral importance of neuroimmune links.

scholarly journals Altered Expression of Peroxiredoxins in Mouse Model of Progressive Myoclonus Epilepsy upon LPS-Induced Neuroinflammation

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 357
Author(s):  
Mojca Trstenjak Prebanda ◽  
Petra Matjan-Štefin ◽  
Boris Turk ◽  
Nataša Kopitar-Jerala
Keyword(s):  
Mouse Model ◽  
Redox Homeostasis ◽  
Underlying Mechanism ◽  
Loss Of Function ◽  
Altered Expression ◽  
Lps Challenge ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy ◽  
The Brain ◽  
Deficient Mice

Stefin B (cystatin B) is an inhibitor of endo-lysosomal cysteine cathepsin, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht–Lundborg disease (EPM1), a form of progressive myoclonus epilepsy. Stefin B-deficient mice, a mouse model of the disease, display key features of EPM1, including myoclonic seizures. Although the underlying mechanism is not yet completely clear, it was reported that the impaired redox homeostasis and inflammation in the brain contribute to the progression of the disease. In the present study, we investigated if lipopolysaccharide (LPS)-triggered neuroinflammation affected the protein levels of redox-sensitive proteins: thioredoxin (Trx1), thioredoxin reductase (TrxR), peroxiredoxins (Prxs) in brain and cerebella of stefin B-deficient mice. LPS challenge was found to result in a marked elevation of Trx1 and TrxR in the brain and cerebella of stefin B deficient mice, while Prx1 was upregulated only in cerebella after LPS challenge. Mitochondrial peroxiredoxin 3 (Prx3), was upregulated also in the cerebellar tissue lysates prepared from unchallenged stefin B deficient mice, while after LPS challenge Prx3 was upregulated in stefin B deficient brain and cerebella. Our results imply the role of oxidative stress in the progression of the disease.

scholarly journals Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joseph J. Rossi ◽  
Jill A. Rosenfeld ◽  
Katie M. Chan ◽  
Haley Streff ◽  
Victoria Nankivell ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Protein Function ◽  
Transcriptional Activity ◽  
Neurodevelopmental Disorder ◽  
Complete Loss ◽  
Loss Of Function ◽  
Targeted Disruption ◽  
Clinical Exome Sequencing ◽  
Partner Protein ◽  
The Brain

AbstractAberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disruption of either gene in mice results in a phenotype resembling ID and SZ. However, there are few human variants in NPAS3 and none in NPAS4 that have been associated with schizophrenia or neurodevelopmental disorders. From a clinical exome sequencing database we identified three NPAS3 variants and four NPAS4 variants that could potentially disrupt protein function in individuals with either developmental delay or ID. The transcriptional activity of the variants when partnered with either ARNT or ARNT2 was assessed by reporter gene activity and it was found that variants which truncated the NPAS3/4 protein resulted in a complete loss of transcriptional activity. The ability of loss-of-function variants to heterodimerise with neuronally enriched partner protein ARNT2 was then determined by co-immunoprecipitation experiments. It was determined that the mechanism for the observed loss of function was the inability of the truncated NPAS3/4 protein to heterodimerise with ARNT2. This further establishes NPAS3 and NPAS4 as candidate neurodevelopmental disorder genes.

scholarly journals A Novel Mutation of ATP7B Gene in a Case of Wilson Disease

Medicina ◽  
2021 ◽  
Vol 57 (2) ◽  
pp. 123
Author(s):  
Cigdem Yuce Kahraman ◽  
Ali Islek ◽  
Abdulgani Tatar ◽  
Özlem Özdemir ◽  
Adil Mardinglu ◽  
...  
Keyword(s):  
Wilson Disease ◽  
Novel Mutation ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Compound Heterozygous ◽  
Atp7b Gene ◽  
Loss Of Function ◽  
Clinical Presentations ◽  
The Family ◽  
The Brain

Wilson disease (WD) (OMIM# 277900) is an autosomal recessive inherited disorder characterized by excess copper (Cu) storage in different human tissues, such as the brain, liver, and the corneas of the eyes. It is a rare disorder that occurs in approximately 1 in 30,000 individuals. The clinical presentations of WD are highly varied, primarily consisting of hepatic and neurological conditions. WD is caused by homozygous or compound heterozygous mutations in the ATP7B gene. The diagnosis of the disease is complicated because of its heterogeneous phenotypes. The molecular genetic analysis encourages early diagnosis, treatment, and the opportunity to screen individuals at risk in the family. In this paper, we reported a case with a novel, hotspot-located mutation in WD. We have suggested that this mutation in the ATP7B gene might contribute to liver findings, progressing to liver failure with a loss of function effect. Besides this, if patients have liver symptoms in childhood and/or are children of consanguineous parents, WD should be considered during the evaluation of the patients.

scholarly journals DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1

2019 ◽  
Vol 116 (50) ◽  
pp. 25322-25328 ◽  
Author(s):  
Yi Liu ◽  
Xiaopin Ma ◽  
Hisashi Fujioka ◽  
Jun Liu ◽  
Shengdi Chen ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Cellular Mechanism ◽  
Loss Of Function ◽  
Wild Type ◽  
Calcium Efflux ◽  
And Function ◽  
The Brain ◽  
Early Onset Parkinson’S Disease

Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson’s disease (PD), yet the underlying pathogenic mechanism remains elusive. Here we demonstrate that DJ-1 localized to the mitochondria-associated membrane (MAM) both in vitro and in vivo. In fact, DJ-1 physically interacts with and is an essential component of the IP3R3-Grp75-VDAC1 complexes at MAM. Loss of DJ-1 disrupted the IP3R3-Grp75-VDAC1 complex and led to reduced endoplasmic reticulum (ER)-mitochondria association and disturbed function of MAM and mitochondria in vitro. These deficits could be rescued by wild-type DJ-1 but not by the familial PD-associated L166P mutant which had demonstrated reduced interaction with IP3R3-Grp75. Furthermore, DJ-1 ablation disturbed calcium efflux-induced IP3R3 degradation after carbachol treatment and caused IP3R3 accumulation at the MAM in vitro. Importantly, similar deficits in IP3R3-Grp75-VDAC1 complexes and MAM were found in the brain of DJ-1 knockout mice in vivo. The DJ-1 level was reduced in the substantia nigra of sporadic PD patients, which was associated with reduced IP3R3-DJ-1 interaction and ER-mitochondria association. Together, these findings offer insights into the cellular mechanism in the involvement of DJ-1 in the regulation of the integrity and calcium cross-talk between ER and mitochondria and suggests that impaired ER-mitochondria association could contribute to the pathogenesis of PD.

scholarly journals Amelioration of Scopolamine-Induced Learning and Memory Impairment byα-Pinene in C57BL/6 Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Gil-Yong Lee ◽  
Chan Lee ◽  
Gyu Hwan Park ◽  
Jung-Hee Jang
Keyword(s):  
Learning And Memory ◽  
Memory Impairment ◽  
Manganese Superoxide Dismutase ◽  
Molecular Mechanisms ◽  
Neuroprotective Effect ◽  
Memory Loss ◽  
Cholinergic Neurons ◽  
Morris Water Maze Test ◽  
Heme Oxygenase 1 ◽  
Related Factor

Increasing evidence suggests that neurodegenerative disorders such as Alzheimer’s disease (AD) are mediated via disruption of cholinergic neurons and enhanced oxidative stress. Therefore, attention has been focused on searching for antioxidant phytochemicals for the prevention and/or treatment of AD through their ability to fortify cholinergic function and antioxidant defense capacity. In this study, we have investigated the neuroprotective effect ofα-pinene (APN) against learning and memory impairment induced by scopolamine (SCO, 1 mg/kg, i.p.), a muscarinic receptor antagonist in C57BL/6 mice. Administration of APN (10 mg/kg, i.p.) significantly improved SCO-induced cognitive dysfunction as assessed by Y-maze and passive avoidance tests. In Morris water-maze test, APN effectively shortened the mean escape latency to find the hidden platform during training days. To further elucidate the molecular mechanisms underlying the neuroprotective effect of APN, the expression of proteins involved in the acetylcholine metabolism and antioxidant system was examined. Particularly, APN treatment increased mRNA expression of choline acetyltransferase in the cortex and protein levels of antioxidant enzymes such as heme oxygenase-1 and manganese superoxide dismutase in the hippocampus via activation of NF-E2-related factor 2. These findings suggest the possible neuroprotective potentials of APN for the management of dementia with learning and memory loss.

Multiple Memory Systems and Their Support of Language

2014 ◽  
Vol 24 (2) ◽  
pp. 64-73 ◽  
Author(s):  
Jake Kurczek ◽  
Natalie Vanderveen ◽  
Melissa C. Duff
Keyword(s):  
Memory Impairment ◽  
Language Use ◽  
Declarative Memory ◽  
Memory Systems ◽  
Memory And Learning ◽  
Multiple Memory Systems ◽  
History Of Research ◽  
Language And Communication ◽  
History Of ◽  
The Brain

There is a long history of research linking the various forms of memory to different aspects of language. Clinically, we see this memory-language connection in the prevalence of language and communication deficits in populations that have concomitant impairments in memory and learning. In this article, we provide an overview of how the demands of language use and processing are supported by multiple memory systems in the brain, including working memory, declarative memory and nondeclarative memory, and how disruptions in different forms of memory may affect language. While not an exhaustive review of the literature, special attention is paid to populations who speech-language pathologists (SLPs) routinely serve. The goal of this review is to provide a resource for clinicians working with clients with disorders in memory and learning in helping to understand and anticipate the range of disruptions in language and communication that can arise as a consequence of memory impairment. We also hope this is a catalyst for more research on the contribution of multiple memory systems to language and communication.

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