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 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 Assisted Movement With Enhanced Sensation (AMES): Coupling Motor and Sensory to Remediate Motor Deficits in Chronic Stroke Patients

2008 ◽  
Vol 23 (1) ◽  
pp. 67-77 ◽  
Author(s):  
Paul Cordo ◽  
Helmi Lutsep ◽  
Linda Cordo ◽  
W. Geoffrey Wright ◽  
Timothy Cacciatore ◽  
...  
Keyword(s):  
Lower Extremity ◽  
Motor Deficits ◽  
Motor Impairments ◽  
Joint Rotation ◽  
Motor Disability ◽  
Stroke Impact Scale ◽  
Impact Scale ◽  
Severe Motor ◽  
The Subject ◽  
Flexion And Extension

Background. Conventional methods of rehabilitation in patients with chronic, severe motor impairments after stroke usually do not lessen paresis. Objective. A novel therapeutic approach (assisted movement with enhanced sensation [AMES]) was employed in a medical device phase I clinical trial to reduce paresis and spasticity and, thereby, to improve motor function. Methods. Twenty subjects more than 1 year poststroke with severe motor disability of the upper or lower extremity were studied. A robotic device cycled the ankle or the wrist and fingers at 5°/s through ±17.5° in flexion and extension while the subject assisted this motion. Feedback of the subject's active torque was displayed on a monitor. Simultaneously, 2 vibrators applied a 60 pps stimulus to the tendons of the lengthening muscles, alternating from flexors to extensors as the joint rotation reversed from extension to flexion, respectively. Subjects treated themselves at home for 30 min/day for 6 months. Every other day prior to treatment, the therapy device performed automated tests of strength and joint positioning. Functional testing was performed prior to enrollment, immediately after completing the protocol, and 6 months later. Functional tests included gait and weight distribution (lower extremity subjects only) and the Stroke Impact Scale. Results. Most subjects improved on most tests, and gains were sustained for 6 months in most subjects. No safety problems arose. Conclusion. The AMES strategy appears safe and possibly effective in patients with severe chronic impairments. The mechanism underlying these gains is likely to be multifactorial.

scholarly journals Cognitive Deficits in the R6/2 mouse model of Huntington’s disease and their Amelioration with Donepezil

2014 ◽  
Vol 27 (3) ◽  
Author(s):  
Carol A. Murphy ◽  
Neil E. Paterson ◽  
Angela Chen ◽  
Washington Arias ◽  
Dansha He ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Psychiatric Symptoms ◽  
Motor Dysfunction ◽  
Cag Repeats ◽  
Motor Deficits ◽  
Cholinergic Function ◽  
Severe Motor

The neurodegenerative disorder Huntington’s disease (HD) is characterized by motor dysfunction, cognitive impairment and psychiatric symptoms. The R6/2 (120 CAG repeats) mouse model of HD recapitulates many of the symptoms of the disease, including marked impairments in cognition and severe motor deficits. As cholinergic function has been reported to be affected in both HD patients and this mouse model, we tested whether treatment with the cholinesterase inhibitor donepezil could improve the R6/2 mice performance in the two-choice swim tank visual discrimination and reversal task. In this test mice are trained to swim towards a light cued platform located on one side of a water-filled tank. Once mice reach an acquisition criterion a reversal ensues. Wild-type and R6/2 mice were dosed with donepezil (0.6 mg/kg/day) or vehicle starting at 8 weeks of age and tested starting at 9 weeks of age. In experiment 1, vehicle-treated R6/2 mice showed a significant deficit during acquisition and reversal as compared to vehicle-treated WT mice. Donepezil improved reversal in the R6/2 group. In experiment 2, we confirmed the beneficial effect of donepezil on reversal in similar conditions. Donepezil had no effect on activity as measured in the open field test or through the latency to reach the platform during the swim test. We suggest that the donepezil-induced improvements in cognitive function observed in the R6/2 transgenic model of HD may reflect amelioration of deficits in cholinergic function that have been reported previously in this model. Further work is required to confirm the findings of these interesting although preliminary studies.

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 Localized chondro-ossification underlies joint dysfunction and motor deficits in the Fkbp10 mouse model of osteogenesis imperfecta

2021 ◽  
Vol 118 (25) ◽  
pp. e2100690118
Author(s):  
Joohyun Lim ◽  
Caressa Lietman ◽  
Matthew W. Grol ◽  
Alexis Castellon ◽  
Brian Dawson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Osteogenesis Imperfecta ◽  
Genetic Disorder ◽  
Motor Deficits ◽  
Type I ◽  
Loss Of Function ◽  
Pathogenic Mechanisms ◽  
Biochemical Alterations ◽  
Fk506 Binding Protein ◽  
Type I Procollagen

Osteogenesis imperfecta (OI) is a genetic disorder that features wide-ranging defects in both skeletal and nonskeletal tissues. Previously, we and others reported that loss-of-function mutations in FK506 Binding Protein 10 (FKBP10) lead to skeletal deformities in conjunction with joint contractures. However, the pathogenic mechanisms underlying joint dysfunction in OI are poorly understood. In this study, we have generated a mouse model in which Fkbp10 is conditionally deleted in tendons and ligaments. Fkbp10 removal substantially reduced telopeptide lysyl hydroxylation of type I procollagen and collagen cross-linking in tendons. These biochemical alterations resulting from Fkbp10 ablation were associated with a site-specific induction of fibrosis, inflammation, and ectopic chondrogenesis followed by joint deformities in postnatal mice. We found that the ectopic chondrogenesis coincided with enhanced Gli1 expression, indicating dysregulated Hedgehog (Hh) signaling. Importantly, genetic inhibition of the Hh pathway attenuated ectopic chondrogenesis and joint deformities in Fkbp10 mutants. Furthermore, Hh inhibition restored alterations in gait parameters caused by Fkbp10 loss. Taken together, we identified a previously unappreciated role of Fkbp10 in tendons and ligaments and pathogenic mechanisms driving OI joint dysfunction.

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.

Association of the Non-Motor Burden with Patterns of Striatal Dopamine Loss in de novo Parkinson’s Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 1541-1549
Author(s):  
Seok Jong Chung ◽  
Sangwon Lee ◽  
Han Soo Yoo ◽  
Yang Hyun Lee ◽  
Hye Sun Lee ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
De Novo ◽  
Early Stage ◽  
Striatal Dopamine ◽  
Motor Deficits ◽  
Dopamine Depletion ◽  
Severe Motor ◽  
Severe Group ◽  
Striatal Dopamine Depletion

Background: Striatal dopamine deficits play a key role in the pathogenesis of Parkinson’s disease (PD), and several non-motor symptoms (NMSs) have a dopaminergic component. Objective: To investigate the association between early NMS burden and the patterns of striatal dopamine depletion in patients with de novo PD. Methods: We consecutively recruited 255 patients with drug-naïve early-stage PD who underwent 18F-FP-CIT PET scans. The NMS burden of each patient was assessed using the NMS Questionnaire (NMSQuest), and patients were divided into the mild NMS burden (PDNMS-mild) (NMSQuest score <6; n = 91) and severe NMS burden groups (PDNMS-severe) (NMSQuest score >9; n = 90). We compared the striatal dopamine transporter (DAT) activity between the groups. Results: Patients in the PDNMS-severe group had more severe parkinsonian motor signs than those in the PDNMS-mild group, despite comparable DAT activity in the posterior putamen. DAT activity was more severely depleted in the PDNMS-severe group in the caudate and anterior putamen compared to that in the PDMNS-mild group. The inter-sub-regional ratio of the associative/limbic striatum to the sensorimotor striatum was lower in the PDNMS-severe group, although this value itself lacked fair accuracy for distinguishing between the patients with different NMS burdens. Conclusion: This study demonstrated that PD patients with severe NMS burden exhibited severe motor deficits and relatively diffuse dopamine depletion throughout the striatum. These findings suggest that the level of NMS burden could be associated with distinct patterns of striatal dopamine depletion, which could possibly indicate the overall pathological burden in PD.

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