Loss of TMEM106B leads to myelination deficits: implications for frontotemporal dementia treatment strategies

Abstract Genetic variants that define two distinct haplotypes at the TMEM106B locus have been implicated in multiple neurodegenerative diseases and in healthy brain ageing. In frontotemporal dementia (FTD), the high expressing TMEM106B risk haplotype was shown to increase susceptibility for FTD with TDP-43 inclusions (FTD-TDP) and to modify disease penetrance in progranulin mutation carriers (FTD-GRN). To elucidate the biological function of TMEM106B and determine whether lowering TMEM106B may be a viable therapeutic strategy, we performed brain transcriptomic analyses in 8-month-old animals from our recently developed Tmem106b−/− mouse model. We included 10 Tmem106b+/+ (wild-type), 10 Tmem106b+/− and 10 Tmem106−/− mice. The most differentially expressed genes (153 downregulated and 60 upregulated) were identified between Tmem106b−/− and wild-type animals, with an enrichment for genes implicated in myelination-related cellular processes including axon ensheathment and oligodendrocyte differentiation. Co-expression analysis also revealed that the most downregulated group of correlated genes was enriched for myelination-related processes. We further detected a significant loss of OLIG2-positive cells in the corpus callosum of Tmem106b−/− mice, which was present already in young animals (21 days) and persisted until old age (23 months), without worsening. Quantitative polymerase chain reaction revealed a reduction of differentiated but not undifferentiated oligodendrocytes cellular markers. While no obvious changes in myelin were observed at the ultrastructure levels in unchallenged animals, treatment with cuprizone revealed that Tmem106b−/− mice are more susceptible to cuprizone-induced demyelination and have a reduced capacity to remyelinate, a finding which we were able to replicate in a newly generated Tmem106b CRISPR/cas9 knock-out mouse model. Finally, using a TMEM106B HeLa knock-out cell line and primary cultured oligodendrocytes, we determined that loss of TMEM106B leads to abnormalities in the distribution of lysosomes and PLP1. Together these findings reveal an important function for TMEM106B in myelination with possible consequences for therapeutic strategies aimed at lowering TMEM106B levels.

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SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models

AJP Cell Physiology ◽

10.1152/ajpcell.00341.2014 ◽

2015 ◽

Vol 308 (9) ◽

pp. C699-C709 ◽

Cited By ~ 23

Author(s):

Davi A. G. Mázala ◽

Stephen J. P. Pratt ◽

Dapeng Chen ◽

Jeffery D. Molkentin ◽

Richard M. Lovering ◽

...

Keyword(s):

Mouse Model ◽

Muscle Damage ◽

Muscle Wasting ◽

Mdx Mice ◽

Functional Impairments ◽

Wild Type ◽

Skeletal Muscle Damage ◽

Threefold Increase ◽

Intracellular Ca ◽

Cellular Markers

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting secondary to repeated muscle damage and inadequate repair. Elevations in intracellular free Ca2+ have been implicated in disease progression, and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1 (SERCA1) overexpression has been shown to ameliorate the dystrophic phenotype in mdx mice. The purpose of this study was to assess the effects of SERCA1 overexpression in the more severe mdx/Utr−/− mouse model of DMD. Mice overexpressing SERCA1 were crossed with mdx/Utr+/− mice to generate mdx/Utr−/−/+SERCA1 mice and compared with wild-type (WT), WT/+SERCA1, mdx/+SERCA1, and genotype controls. Mice were assessed at ∼12 wk of age for changes in Ca2+ handling, muscle mass, quadriceps torque, markers of muscle damage, and response to repeated eccentric contractions. SERCA1-overexpressing mice had a two- to threefold increase in maximal sarcoplasmic reticulum Ca2+-ATPase activity compared with WT which was associated with normalization in body mass for both mdx/+SERCA1 and mdx/Utr−/−/+SERCA1. Torque deficit in the quadriceps after eccentric injury was 2.7-fold greater in mdx/Utr−/− vs. WT mice, but only 1.5-fold greater in mdx/Utr−/−/+SERCA1 vs. WT mice, an attenuation of 44%. Markers of muscle damage (% centrally nucleated fibers, necrotic area, and serum creatine kinase levels) were higher in both mdx and mdx/Utr−/− vs. WT, and all were attenuated by overexpression of SERCA1. These data indicate that SERCA1 overexpression ameliorates functional impairments and cellular markers of damage in a more severe mouse model of DMD. These findings support targeting intracellular Ca2+ control as a therapeutic approach for DMD.

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Neurocognitive endophenotypes in CGG KI and Fmr1 KO mouse models of Fragile X-Associated disorders: an analysis of the state of the field

F1000Research ◽

10.12688/f1000research.2-287.v1 ◽

2013 ◽

Vol 2 ◽

pp. 287 ◽

Cited By ~ 5

Author(s):

Michael R. Hunsaker

Keyword(s):

Mouse Model ◽

Mouse Models ◽

Trinucleotide Repeat ◽

Fragile X ◽

Treatment Strategies ◽

Preliminary Evidence ◽

Future Research ◽

Behavioral Experiments ◽

Knock Out ◽

Fragile X Premutation

It has become increasingly important that the field of behavioral genetics identifies not only the gross behavioral phenotypes associated with a given mutation, but also the behavioral endophenotypes that scale with the dosage of the particular mutation being studied. Over the past few years, studies evaluating the effects of the polymorphic CGG trinucleotide repeat on theFMR1gene underlying Fragile X-Associated Disorders have reported preliminary evidence for a behavioral endophenotype in human Fragile X Premutation carrier populations as well as the CGG knock-in (KI) mouse model. More recently, the behavioral experiments used to test the CGG KI mouse model have been extended to theFmr1knock-out (KO) mouse model. When combined, these data provide compelling evidence for a clear neurocognitive endophenotype in the mouse models of Fragile X-Associated Disorders such that behavioral deficits scale predictably with genetic dosage. Similarly, it appears that the CGG KI mouse effectively models the histopathology in Fragile X-Associated Disorders across CGG repeats well into the full mutation range, resulting in a reliable histopathological endophenotype. These endophenotypes may influence future research directions into treatment strategies for not only Fragile X Syndrome, but also the Fragile X Premutation and Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).

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Effect of Dietary Zinc Supplementation on the Gastrointestinal Microbiota and Host Gene Expression in the Shank3B-/- Mouse Model of Autism Spectrum Disorder

10.21203/rs.3.rs-864668/v1 ◽

2021 ◽

Author(s):

Giselle C Wong ◽

Yewon Jung ◽

Kevin Lee ◽

Chantelle Fourie ◽

Kim M. Handley ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Mouse Model ◽

Gut Microbiota ◽

Gut Microbiome ◽

Autism Spectrum ◽

Wild Type ◽

Dietary Zinc ◽

Knock Out ◽

Gastrointestinal Problems ◽

Host Metabolism

Abstract Background: Shank genes are implicated in ~1% of people with autism and mice with Shank3 knock out mutations exhibit autism-like behaviours. Zinc deficiency and gastrointestinal problems can be common among people with autism, and zinc is a key element required for SHANK protein function and gut development. In Shank3B-/- mice, a supplementary zinc diet reverses autism behaviours. We hypothesise that dietary zinc may alter the gut microbiome, potentially affecting the gut-microbiota-brain axis, which may contribute to changes in autism-like behaviours. Methods: Four types of gastrointestinal samples (ileum, caecum, colon, faecal) were collected from wild-type and knock-out Shank3B-/- mice on either control or supplemented-zinc diets. Bacterial 16S rRNA gene and fungal ITS2 genomic region amplicons were sequenced on the Illumina MiSeq platform and RNA on the Illumina HiSeq platform.Results: Cage, genotype and zinc diet each contributed significantly to bacterial community variation (accounting for 12.8%, 3.9% and 2.3% of the variation, respectively). Fungal diversity differed significantly between wild-type and knock-out Shank3B-/- mice on the control zinc diet, and the fungal biota differed among gut locations. RNA-seq analysis of host (mouse) transcripts revealed differential expression of genes involved in host metabolism that may be regulated by the gut microbiota and genes involved in anti-microbial interactions. Limitations: This study used the Shank3B-/- mouse model of autism spectrum disorder. Heterozygous and homozygous Shank3 gene mutations are found in 1% of the ASD population, only homozygous Shank3 mice were utilised in this study. Any translational conclusions should consider these limitations.Conclusions: By utilising the Shank3B-/- knock-out mouse model we were able to examine the influence of – and interactions between – dietary zinc and ASD-linked host genotype. Differential expression of host antimicrobial interaction genes as well as gut microbiota-regulated host metabolism genes among the treatment groups, suggests that the interplay between gut microbes, the gastrointestinal tract and the brain may play a major role towards the observed amelioration of ASD behaviours seen previously with supplemented dietary zinc. These data broaden understanding of the gut microbiome in autism and pave the way towards potential microbial therapeutics for gastrointestinal problems in people with autism.

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Effect of dietary zinc supplementation on the gastrointestinal microbiota and host gene expression in the Shank3B−/− mouse model of autism spectrum disorder

10.1101/2021.09.09.459709 ◽

2021 ◽

Author(s):

Giselle C. Wong ◽

Yewon Jung ◽

Kevin Lee ◽

Chantelle Fourie ◽

Kim M. Handley ◽

...

Keyword(s):

Mouse Model ◽

Gut Microbiome ◽

Autism Spectrum ◽

Wild Type ◽

Dietary Zinc ◽

Host Genotype ◽

Knock Out ◽

Treatment Groups ◽

Gastrointestinal Problems ◽

Host Metabolism

AbstractShank genes are implicated in ~1% of people with autism and mice with Shank3 knock out mutations exhibit autism-like behaviours. Zinc deficiency and gastrointestinal problems can be common among people with autism, and zinc is a key element required for SHANK protein function and gut development. In Shank3B−/− mice, a supplementary zinc diet reverses autism behaviours. We hypothesise that dietary zinc may alter the gut microbiome, potentially affecting the gut-microbiome-brain axis, which may contribute to changes in autism-like behaviours. To test this, four types of gastrointestinal samples (ileum, caecum, colon, faecal) were collected from wild-type and knock-out Shank3B−/− mice on either control or supplemented-zinc diets. Cage, genotype and zinc diet each contributed significantly to bacterial community variation (accounting for 12.8%, 3.9% and 2.3% of the variation, respectively). Fungal diversity differed significantly between wild-type and knock-out Shank3B−/− mice on the control zinc diet, and the fungal biota differed among gut locations. RNA-seq analysis of host (mouse) transcripts revealed differential expression of genes involved in host metabolism that may be regulated by the gut microbiota and genes involved in anti-microbial interactions. By utilising the Shank3B−/− knock-out mouse model we were able to examine the influence of – and interactions between – dietary zinc and ASD-linked host genotype. These data broaden understanding of the gut microbiome in autism and pave the way towards potential microbial therapeutics for gastrointestinal problems in people with autism.ImportancePreviously, supplemental dietary zinc in the Shank3B−/− mouse model of autism spectrum disorder resulted in observations of ASD behaviours reversal; in this study we also used the Shank3B−/− mouse model to examine the influence of – and interaction between – dietary zinc and ASD-linked host genotype. Sample location along the gastrointestinal tract, genotype and zinc diet explained some of the variation in the microbiota data, with notable bacterial differences between treatment groups. Differential expression of host genes between treatment groups, including antimicrobial interaction genes and gut microbiota-regulated host metabolism genes, suggests that the interplay between gut microbes, the gastrointestinal tract and the brain may play a major role towards the observed amelioration of ASD behaviours seen previously with supplemented dietary zinc. These results widen the scope towards manipulating both dietary zinc and the microbiota itself to ameliorate ASD-related behaviours and associated gastrointestinal issues.

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Non-ionotropic NMDA receptor signaling alters structural plasticity of dendritic spines in a mouse model of schizophrenia

10.1101/2021.03.04.434016 ◽

2021 ◽

Author(s):

Deborah K Park ◽

Ivar S Stein ◽

Eden V Barragan ◽

John A Gray ◽

Karen Zito

Keyword(s):

Nmda Receptor ◽

Mouse Model ◽

Psychiatric Disorder ◽

Dendritic Spines ◽

Ion Flux ◽

Wild Type ◽

Knock Out ◽

Aspartate Receptor ◽

Hippocampal Synapses ◽

Activity Dependent

Schizophrenia is a psychiatric disorder that affects over 20 million people globally. Notably, schizophrenia is associated with decreased density of dendritic spines and decreased levels of D-serine, a co-agonist of the N-methyl-D-aspartate receptor (NMDAR), and hypofunction of NMDARs is thought to play a role in the pathophysiology of schizophrenia. We hypothesized that lowered D-serine levels associated with schizophrenia would bias toward ion flux-independent signaling by the NMDAR, which drives spine shrinkage and loss. Using a schizophrenia mouse model lacking the enzyme for D-serine production (serine racemase knock out; SRKO), we show that activity-dependent spine growth is inhibited in SRKO mice but can be acutely rescued by exogenous D-serine. When examining a wider range of stimulus strengths, we observed activity-dependent spine growth at higher stimulus strengths, but overall found a strong bias toward spine shrinkage in the SRKO mice as compared to wild-type littermates. Furthermore, we demonstrate that enhanced ion flux-independent signaling through the NMDAR contributes to this bias toward spine shrinkage, which is likely exacerbated by an increase in synaptic NMDARs in hippocampal synapses of SRKO mice. Our results support a model in which the lowered D-serine levels associated with schizophrenia lead to increased ion flux-independent NMDAR signaling and a bias toward spine shrinkage that could play an important role in the loss of dendritic spines associated with schizophrenia.

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Functional characterization of the H+/K+ ATPase in wild type and gastrin knock-out mice

Zeitschrift für Gastroenterologie ◽

10.1055/s-2007-982721 ◽

2007 ◽

Vol 45 (05) ◽

Author(s):

A Schnur ◽

P Hegyi ◽

V Venglovecz ◽

Z Rakonczay ◽

I Ignáth ◽

...

Keyword(s):

Functional Characterization ◽

Wild Type ◽

Knock Out ◽

Knock Out Mice

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Dysregulation of DNA methylation during development as a potential mechanisms contributing to obsessive compulsive disorders and autism

10.31234/osf.io/udfya ◽

2019 ◽

Author(s):

German I. Todorov ◽

Karthikeyan Mayilvahanan ◽

David Ashurov ◽

Catarina Cunha

Keyword(s):

Mouse Model ◽

Autism Spectrum ◽

Obsessive Compulsive ◽

Cancer Treatments ◽

Knock Out ◽

Treatment Priority ◽

Underlying Mechanisms ◽

Knock Out Mice ◽

Obsessive Compulsive Disorders ◽

Compulsive Disorders

Autism Spectrum Disorder (ASD) is a pervasive developmental disorder, that is raising at a concerning rate. However, underlying mechanisms are still to be discovered. Obsessions and compulsions are the most debilitating aspect of these disorders (OCD), and they are the treatment priority for patients. SAPAP3 knock out mice present a reliable mouse model for repetitive compulsive behavior and are mechanistically closely related to the ASD mouse model Shank3 on a molecular level and AMPA receptor net effect. The phenotype of SAPAP3 knock out mice is obsessive grooming that leads to self-inflicted lesions by 4 months of age. Recent studies have accumulated evidence, that epigenetic mechanisms are important effectors in psychiatric conditions such as ASD and OCD. Methylation is the most studied mechanism, that recently lead to drug developments for more precise cancer treatments. We injected SAPAP3 mice with an epigenetic demethylation drug RG108 during pregnancy and delayed the onset of the phenotype in the offspring by 4 months. This result gives us clues about possible mechanism involved in OCD and ASD. Additionally, it shows that modulation of methylation mechanisms during development might be explored as a preventative treatment in the cases of high inherited risk of certain mental health conditions.

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