scholarly journals Genetic Disruption of WASHC4 Drives Endo-lysosomal Dysfunction and Cognitive-Movement Impairments in Mice and Humans

2020 ◽  
Author(s):  
Jamie L. Courtland ◽  
Tyler W. A. Bradshaw ◽  
Greg Waitt ◽  
Erik J. Soderblom ◽  
Tricia Ho ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Retrospective Analysis ◽  
Mouse Brain ◽  
Motor Deficits ◽  
Motor Impairments ◽  
Proteomics Analysis ◽  
Lysosomal Dysfunction ◽  
The Brain ◽  
Progressive Motor Deficits

ABSTRACTMutation of the WASH complex subunit, SWIP, is implicated in human intellectual disability, but the cellular etiology of this association is unknown. We identify the neuronal WASH complex proteome, revealing a network of endosomal proteins. To uncover how dysfunction of endosomal SWIP leads to disease, we generate a mouse model of the human WASHC4c.3056C>G mutation. Quantitative spatial proteomics analysis of SWIPP1019R mouse brain reveals that this mutation destabilizes the WASH complex and uncovers significant perturbations in both endosomal and lysosomal pathways. Cellular and histological analyses confirm that SWIPP1019R results in endo-lysosomal disruption and uncover indicators of neurodegeneration. We find that SWIPP1019R not only impacts cognition, but also causes significant progressive motor deficits in mice. Remarkably, a retrospective analysis of SWIPP1019R patients confirms motor deficits in humans. Combined, these findings support the model that WASH complex destabilization, resulting from SWIPP1019R, drives cognitive and motor impairments via endo-lysosomal dysfunction in the brain.

scholarly journals Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement impairments in mice and humans

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jamie L Courtland ◽  
Tyler WA Bradshaw ◽  
Greg Waitt ◽  
Erik J Soderblom ◽  
Tricia Ho ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Retrospective Analysis ◽  
Motor Deficits ◽  
Motor Impairments ◽  
Proteomics Analysis ◽  
Lysosomal Dysfunction ◽  
Syndrome Protein ◽  
The Brain ◽  
Progressive Motor Deficits

Mutation of the Wiskott–Aldrich syndrome protein and SCAR homology (WASH) complex subunit, SWIP, is implicated in human intellectual disability, but the cellular etiology of this association is unknown. We identify the neuronal WASH complex proteome, revealing a network of endosomal proteins. To uncover how dysfunction of endosomal SWIP leads to disease, we generate a mouse model of the human WASHC4c.3056C>G mutation. Quantitative spatial proteomics analysis of SWIPP1019R mouse brain reveals that this mutation destabilizes the WASH complex and uncovers significant perturbations in both endosomal and lysosomal pathways. Cellular and histological analyses confirm that SWIPP1019R results in endo-lysosomal disruption and uncover indicators of neurodegeneration. We find that SWIPP1019R not only impacts cognition, but also causes significant progressive motor deficits in mice. A retrospective analysis of SWIPP1019R patients reveals similar movement deficits in humans. Combined, these findings support the model that WASH complex destabilization, resulting from SWIPP1019R, drives cognitive and motor impairments via endo-lysosomal dysfunction in the brain.

scholarly journals Gait Analysis in a Mecp2 Knockout Mouse Model of Rett Syndrome Reveals Early-Onset and Progressive Motor Deficits

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e112889 ◽  
Author(s):  
Kamal K. E. Gadalla ◽  
Paul D. Ross ◽  
John S. Riddell ◽  
Mark E. S. Bailey ◽  
Stuart R. Cobb
Keyword(s):  
Mouse Model ◽  
Gait Analysis ◽  
Rett Syndrome ◽  
Early Onset ◽  
Knockout Mouse ◽  
Motor Deficits ◽  
Knockout Mouse Model ◽  
Progressive Motor Deficits

Caffeine alleviates progressive motor deficits in a transgenic mouse model of spinocerebellar ataxia

2017 ◽  
Vol 81 (3) ◽  
pp. 407-418 ◽  
Author(s):  
Nélio Gonçalves ◽  
Ana T. Simões ◽  
Rui D. Prediger ◽  
Hirokazu Hirai ◽  
Rodrigo A. Cunha ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Spinocerebellar Ataxia ◽  
Transgenic Mouse Model ◽  
Motor Deficits ◽  
Progressive Motor Deficits

scholarly journals Tendon and Motor Phenotypes in the Crtap-/- Mouse Model of Recessive Osteogenesis Imperfecta

2020 ◽  
Author(s):  
Matthew W. Grol ◽  
Nele A. Haelterman ◽  
Joohyun Lim ◽  
Elda M. Munivez ◽  
Marilyn Archer ◽  
...  
Keyword(s):  
Mouse Model ◽  
Osteogenesis Imperfecta ◽  
Bone Fragility ◽  
Joint Hypermobility ◽  
Motor Deficits ◽  
Motor Impairments ◽  
Matrix Gene ◽  
Severe Motor ◽  
Cross Links ◽  
Immature Cells

ABSTRACTOsteogenesis imperfecta (OI) is characterized by short stature, skeletal deformities, low bone mass with bone fragility, and motor deficits. A subset of OI patients also present with joint hypermobility; however, the role of tendon/ligament dysfunction in OI pathogenesis is largely unknown. Using the Crtap-/- mouse model of severe, recessive OI, we found that mutant Achilles tendons and patellar ligaments were thinner with increased collagen cross-links and reduced collagen fibril size at 1- and 4-months compared to wildtype. Patellar ligaments from Crtap-/- mice also had fewer progenitors with a concomitant increase in immature cells. RNA-seq analysis of Achilles tendons and patellar ligaments from 1-month Crtap-/- mice revealed dysregulation in matrix gene expression concomitant with predicted alterations in TGF-β, inflammatory, and metabolic signaling. Finally, a series of behavioral tests revealed severe motor impairments and reduced grip strength in 4-month Crtap-/- mice – a phenotype that correlates with the tendon/ligament pathology.

scholarly journals Azole Heteroresistance in Cryptococcus neoformans: Emergence of Resistant Clones with Chromosomal Disomy in the Mouse Brain during Fluconazole Treatment

2013 ◽  
Vol 57 (10) ◽  
pp. 5127-5130 ◽  
Author(s):  
Edward Sionov ◽  
Yun C. Chang ◽  
Kyung J. Kwon-Chung
Keyword(s):  
Mouse Model ◽  
Cryptococcus Neoformans ◽  
Mouse Brain ◽  
Content Type ◽  
The Brain ◽  
Strain Dependent ◽  
Is Strain

ABSTRACTWe have previously reported thatCryptococcus neoformansstrains are innately heteroresistant to fluconazolein vitro, producing minor, highly resistant subpopulations due to adaptive formation of disomic chromosomes. Using a mouse model, we assessed the emergence of heteroresistant clones in the brain during fluconazole treatment and found that the occurrence of heteroresistant clonesin vivowith chromosomal disomy is strain dependent. Interestingly, emergence of heteroresistant clonesin vivowas unrelated to the strain's MIC to fluconazole.

Intranasal delivery of phenytoin-loaded nanoparticles to the brain suppresses pentylenetetrazol-induced generalized tonic clonic seizures in epilepsy mouse model

2021 ◽  
Author(s):  
Amal Yousfan ◽  
Noelia Rubio Carrero ◽  
Mohamad Al-Ali ◽  
Abdul Hakim Nattouf ◽  
Houmam Kafa
Keyword(s):  
Mouse Model ◽  
Mouse Brain ◽  
Chitosan Nanoparticles ◽  
Intranasal Delivery ◽  
Anti Epileptic Drug ◽  
Clonic Seizures ◽  
The Brain

In this work we describe the preparation and characterization of lecithin-chitosan nanoparticles (L10Ci+), and investigate their ability to deliver the anti-epileptic drug phenytoin (PHT) to mouse brain following intranasal (IN)...

scholarly journals Tendon and motor phenotypes in the Crtap-/- mouse model of recessive Osteogenesis Imperfecta

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Matthew William Grol ◽  
Nele A Haelterman ◽  
Joohyun Lim ◽  
Elda M Munivez ◽  
Marilyn Archer ◽  
...  
Keyword(s):  
Mouse Model ◽  
Osteogenesis Imperfecta ◽  
Skeletal Maturity ◽  
Marker Gene ◽  
Joint Hypermobility ◽  
Motor Deficits ◽  
Matrix Remodeling ◽  
Motor Impairments ◽  
Severe Motor ◽  
Cross Links

Osteogenesis imperfecta (OI) is characterized by short stature, skeletal deformities, low bone mass, and motor deficits. A subset of OI patients also present with joint hypermobility; however, the role of tendon dysfunction in OI pathogenesis is largely unknown. Using the Crtap-/- mouse model of severe, recessive OI, we found that mutant Achilles and patellar tendons were thinner and weaker with increased collagen cross-links and reduced collagen fibril size at 1- and 4-months compared to wildtype. Patellar tendons from Crtap-/- mice also had altered numbers of CD146+CD200+ and CD146-CD200+ progenitor-like cells at skeletal maturity. RNA-seq analysis of Achilles and patellar tendons from 1-month Crtap-/- mice revealed dysregulation in matrix and tendon marker gene expression concomitant with predicted alterations in TGF-b, inflammatory, and metabolic signaling. At 4-months, Crtap-/- mice showed increased aSMA, MMP2, and phospho-NFkB in the patellar tendon consistent with excess matrix remodeling and tissue inflammation. Finally, a series of behavioral tests showed severe motor impairments and reduced grip strength in 4-month Crtap-/- mice – a phenotype that correlates with the tendon pathology.

scholarly journals Fecal microbiota transplantation protects rotenone-induced Parkinson’s disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Zhe Zhao ◽  
Jingwen Ning ◽  
Xiu-qi Bao ◽  
Meiyu Shang ◽  
Jingwei Ma ◽  
...  
Keyword(s):  
Mouse Model ◽  
Gut Microbiota ◽  
Signaling Pathway ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Motor Deficits ◽  
Tlr4 Signaling ◽  
Tlr4 Signaling Pathway ◽  
The Brain ◽  
Gut Microbiota Dysbiosis

Abstract Background Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, displaying not only well-known motor deficits but also gastrointestinal dysfunctions. Consistently, it has been increasingly evident that gut microbiota affects the communication between the gut and the brain in PD pathogenesis, known as the microbiota-gut-brain axis. As an approach to re-establishing a normal microbiota community, fecal microbiota transplantation (FMT) has exerted beneficial effects on PD in recent studies. Here, in this study, we established a chronic rotenone-induced PD mouse model to evaluate the protective effects of FMT treatment on PD and to explore the underlying mechanisms, which also proves the involvement of gut microbiota dysbiosis in PD pathogenesis via the microbiota-gut-brain axis. Results We demonstrated that gut microbiota dysbiosis induced by rotenone administration caused gastrointestinal function impairment and poor behavioral performances in the PD mice. Moreover, 16S RNA sequencing identified the increase of bacterial genera Akkermansia and Desulfovibrio in fecal samples of rotenone-induced mice. By contrast, FMT treatment remarkably restored the gut microbial community, thus ameliorating the gastrointestinal dysfunctions and the motor deficits of the PD mice. Further experiments revealed that FMT administration alleviated intestinal inflammation and barrier destruction, thus reducing the levels of systemic inflammation. Subsequently, FMT treatment attenuated blood-brain barrier (BBB) impairment and suppressed neuroinflammation in the substantia nigra (SN), which further decreased the damage of dopaminergic neurons. Additional mechanistic investigation discovered that FMT treatment reduced lipopolysaccharide (LPS) levels in the colon, the serum, and the SN, thereafter suppressing the TLR4/MyD88/NF-κB signaling pathway and its downstream pro-inflammatory products both in the SN and the colon. Conclusions Our current study demonstrates that FMT treatment can correct the gut microbiota dysbiosis and ameliorate the rotenone-induced PD mouse model, in which suppression of the inflammation mediated by the LPS-TLR4 signaling pathway both in the gut and the brain possibly plays a significant role. Further, we prove that rotenone-induced microbiota dysbiosis is involved in the genesis of PD via the microbiota-gut-brain axis.

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