{"title":"Striatal parvalbumin interneurons, not cholinergic interneurons, are activated in a mouse model of cerebellar dystonia.","authors":"Taku Matsuda, Ryoma Morigaki, Hiroaki Hayasawa, Hiroshi Koyama, Teruo Oda, Kazuhisa Miyake, Yasushi Takagi","doi":"10.1242/dmm.050338","DOIUrl":"https://doi.org/10.1242/dmm.050338","url":null,"abstract":"Dystonia is supposed to arise from abnormalities in the motor loop of the basal ganglia; however, there is an ongoing debate regarding cerebellar involvement. We adopted the established cerebellar dystonia mice model by injecting ouabain to examine the contribution of the cerebellum. Initially, we examined whether the entopeduncular nucleus (EPN), substantia nigra pars reticulata (SNr), globus pallidus externus (GPe), and striatal neurons were activated in the model. Next, we examined whether dopamine D1 receptor agonists (D1 agonist) and dopamine D2 receptor antagonists (D2 antagonist) or selective ablation of striatal parvalbumin (PV) interneurons could modulate their involuntary movements. The cerebellar dystonia mice had a higher number of c-fos-positive cells in the EPN, SNr, and GPe, as well as a higher positive ratio of c-fos in striatal PV interneurons than the control mice. Furthermore, systemic administration of combined D1 agonist and D2 antagonist and selective ablation of striatal PV interneurons relieved their involuntary movements. Abnormalities in the motor loop of the basal ganglia could be crucially involved in cerebellar dystonia, and modulating PV interneurons might provide a novel treatment strategy.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Katerina Mardilovich, Gregory Naylor, Linda Julian, Narisa Phinichkusolchit, Karen Keeshan, Karen Blyth, Michael F Olson
{"title":"Caspase-resistant ROCK1 expression prolongs survival of Eµ-Myc B cell lymphoma mice.","authors":"Katerina Mardilovich, Gregory Naylor, Linda Julian, Narisa Phinichkusolchit, Karen Keeshan, Karen Blyth, Michael F Olson","doi":"10.1242/dmm.050631","DOIUrl":"https://doi.org/10.1242/dmm.050631","url":null,"abstract":"Apoptosis is characterized by membrane blebbing and apoptotic body formation. Caspase cleavage of ROCK1 generates an active fragment that promotes actin-myosin mediated contraction and membrane blebbing during apoptosis. Expression of caspase-resistant non-cleavable ROCK1 (Rock1 NC) prolonged survival of mice that rapidly develop B cell lymphomas due to Eµ-Myc transgene expression. Eµ-Myc; Rock1 NC mice had significantly fewer bone marrow cells relative to Eµ-Myc mice expressing wild-type ROCK1 (Rock1 WT), which was associated with altered cell cycle profiles. Circulating macrophage numbers were lower in Eµ-Myc; Rock1 NC mice, but there were higher levels of bone marrow macrophages, consistent with spontaneous cell death in Eµ-Myc; Rock1 NC mice bone marrows being more inflammatory. Rock1 WT recipient mice transplanted with pre-neoplastic Eµ-Myc; Rock1 NC bone marrow cells survived longer than mice transplanted with Eµ-Myc; Rock1 WT cells, indicating that the survival benefit was intrinsic to the Eµ-Myc; Rock1 NC bone marrow cells. The results suggest that the apoptotic death of Eµ-Myc; Rock1 NC cells generates a proliferation-suppressive microenvironment in bone marrows that reduces cell numbers and prolongs B cell lymphoma mouse survival.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
F C C van Rhijn-Brouwer, K E Wever, R Kiffen, J R van Rhijn, H Gremmels, J O Fledderus, R W M Vernooij, M C Verhaar
{"title":"The effect of bone marrow derived cell therapies on hind limb perfusion, A systematic review and meta-analysis.","authors":"F C C van Rhijn-Brouwer, K E Wever, R Kiffen, J R van Rhijn, H Gremmels, J O Fledderus, R W M Vernooij, M C Verhaar","doi":"10.1242/dmm.050632","DOIUrl":"https://doi.org/10.1242/dmm.050632","url":null,"abstract":"Administration of bone marrow (BM) derived cells to restore perfusion showed promising results in preclinical studies. However, clinical studies in chronic limb threatening ischemia (CLTI) demonstrated conflicting results. We conducted a systematic review and meta-analysis on preclinical studies to assess the efficacy of BM-derived cell administration in restoring relative perfusion in the hind limb ischemia model (HLI) and identify possible determinants of therapeutic efficacy.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rui Lois Tan, Francesca Sciandra, Wolfgang Hübner, Manuela Bozzi, Jens Reimann, Susanne Schoch, Andrea Brancaccio, Sandra Blaess
{"title":"Missense mutation (C667F) in murine β-dystroglycan causes embryonic lethality, myopathy and blood-brain barrier destabilization.","authors":"Rui Lois Tan, Francesca Sciandra, Wolfgang Hübner, Manuela Bozzi, Jens Reimann, Susanne Schoch, Andrea Brancaccio, Sandra Blaess","doi":"10.1242/dmm.050594","DOIUrl":"https://doi.org/10.1242/dmm.050594","url":null,"abstract":"Dystroglycan (DG) is an extracellular matrix receptor consisting of an α- and a β-DG subunit encoded by the DAG1 gene. The homozygous mutation (c.2006G>T, p.Cys669Phe) in β-DG causes Muscle-Eye-Brain disease with multicystic leukodystrophy in humans. In a mouse model of this primary dystroglycanopathy, approximately two-thirds of homozygous embryos fail to develop to term. Mutant mice that are born undergo a normal postnatal development but show a late-onset myopathy with partially penetrant histopathological changes and an impaired performance on an activity wheel. Their brains and eyes are structurally normal, but the localization of mutant β-DG is altered in the glial perivascular endfeet resulting in a perturbed protein composition of the blood-brain and blood-retina barrier. In addition, α- and β-DG protein levels are significantly reduced in muscle and brain of mutant mice. Due to the partially penetrant developmental phenotype of the C669F-β-DG mice, they represent a novel and highly valuable mouse model to study the molecular effects of β-DG functional alterations both during embryogenesis and in mature muscle, brain and eye, and to gain insight into the pathogenesis of primary dystroglycanopathies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140592064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Promoting mitochondrial dynamics by inhibiting the PINK1/PRKN pathway to relieve diabetic nephropathy.","authors":"Jun-Yi Zhu, Joyce van de Leemput, Zhe Han","doi":"10.1242/dmm.050471","DOIUrl":"https://doi.org/10.1242/dmm.050471","url":null,"abstract":"Diabetes is a metabolic disorder characterized by high blood glucose levels and is a leading cause of kidney disease. Diabetic nephropathy has been attributed to dysfunctional mitochondria. However, many questions remain about the exact mechanism. The structure, function, and molecular pathways between mammalian podocytes and Drosophila nephrocytes are highly conserved, therefore we used flies on a high-sucrose diet to model type 2 diabetic nephropathy. The nephrocytes of high-sucrose diet flies showed significant functional decline and decreased cell size, associated with a shortened lifespan. Structurally, the nephrocytes filtration structure known as the slit diaphragm was disorganized. At the cellular level, we found altered mitochondrial dynamics and dysfunction. Regulating mitochondrial dynamics by either genetic modification of the Pink1/Park (mammalian PINK1/PRKN) pathway or treatment with BGP-15, mitigated the mitochondrial defects and nephrocyte functional decline. These findings support a role for Pink1/Park-mediated mitophagy and associated control of mitochondrial dynamics, essential for function, in diabetic nephropathy; and demonstrate that targeting this pathway might provide therapeutic benefits in type 2 diabetic nephropathy.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140592148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kristy Swiderski, Audrey S Chan, Marco J Herold, Andrew J Kueh, Jin D Chung, Justin P Hardee, Jennifer Trieu, Annabel Chee, Timur Naim, Paul Gregorevic, Gordon S Lynch
{"title":"The BALB/c.mdx62 mouse exhibits a dystrophic muscle pathology and is a novel model of Duchenne muscular dystrophy.","authors":"Kristy Swiderski, Audrey S Chan, Marco J Herold, Andrew J Kueh, Jin D Chung, Justin P Hardee, Jennifer Trieu, Annabel Chee, Timur Naim, Paul Gregorevic, Gordon S Lynch","doi":"10.1242/dmm.050502","DOIUrl":"https://doi.org/10.1242/dmm.050502","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is a devastating monogenic skeletal muscle wasting disorder. While many pharmacological and genetic interventions have been reported in preclinical studies, few have progressed to clinical trials with meaningful benefit. Identifying therapeutic potential may be limited by availability of suitable preclinical mouse models. More rigorous testing across models with varied background strains and mutations may identify treatments for clinical success. Here we report the generation of a DMD mouse model, with a CRISPR-induced deletion within exon 62 of the Dmd gene, and the first generated in BALB/c mice. Analysis of mice at 3, 6, and 12 months of age confirmed loss of Dp427 protein expression and resultant dystrophic pathology in limb muscles and the diaphragm, with evidence of centrally nucleated fibers, increased inflammatory markers and fibrosis, progressive decline in muscle function, and compromised trabecular bone development. The C.mdx62 mouse is a novel model of DMD with associated variations in the immune response and muscle phenotype, compared with existing models. It represents an important addition to the preclinical model toolbox for developing therapeutic strategies.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Millet, Corentin Coustham, Camille Champigny, Nadege Merabet, Marlène Botella, Christine Demeilliers, Anne Devin, Anne Galinier, Pascale Belenguer, Joel Bordeneuve-Guibé, N. Davezac
{"title":"Correction: OPA1 deficiency impairs oxidative metabolism in cycling cells, underlining a translational approach for degenerative diseases.","authors":"A. Millet, Corentin Coustham, Camille Champigny, Nadege Merabet, Marlène Botella, Christine Demeilliers, Anne Devin, Anne Galinier, Pascale Belenguer, Joel Bordeneuve-Guibé, N. Davezac","doi":"10.1242/dmm.050815","DOIUrl":"https://doi.org/10.1242/dmm.050815","url":null,"abstract":"","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140797090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Dmd mdx mice have defective oligodendrogenesis, delayed myelin compaction and persistent hypomyelination.","authors":"Andrea J Arreguin, Zijian Shao, Holly Colognato","doi":"10.1242/dmm.050115","DOIUrl":"10.1242/dmm.050115","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, resulting in the loss of dystrophin, a large cytosolic protein that links the cytoskeleton to extracellular matrix receptors in skeletal muscle. Aside from progressive muscle damage, many patients with DMD also have neurological deficits of unknown etiology. To investigate potential mechanisms for DMD neurological deficits, we assessed postnatal oligodendrogenesis and myelination in the Dmdmdx mouse model. In the ventricular-subventricular zone (V-SVZ) stem cell niche, we found that oligodendrocyte progenitor cell (OPC) production was deficient, with reduced OPC densities and proliferation, despite a normal stem cell niche organization. In the Dmdmdx corpus callosum, a large white matter tract adjacent to the V-SVZ, we also observed reduced OPC proliferation and fewer oligodendrocytes. Transmission electron microscopy further revealed significantly thinner myelin, an increased number of abnormal myelin structures and delayed myelin compaction, with hypomyelination persisting into adulthood. Our findings reveal alterations in oligodendrocyte development and myelination that support the hypothesis that changes in diffusion tensor imaging seen in patients with DMD reflect developmental changes in myelin architecture.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140891813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sheeza Mughal, Maria Sabater-Arcis, R. Artero, J. Ramón‐Azcón, J. Fernández‐Costa
{"title":"Taurine activates the AKT-mTOR axis to restore muscle mass and contractile strength in human 3D in vitro models of steroid myopathy.","authors":"Sheeza Mughal, Maria Sabater-Arcis, R. Artero, J. Ramón‐Azcón, J. Fernández‐Costa","doi":"10.1242/dmm.050540","DOIUrl":"https://doi.org/10.1242/dmm.050540","url":null,"abstract":"Steroid myopathy is a clinically challenging condition exacerbated by prolonged corticosteroid use or adrenal tumors. In this study, we engineered a functional three-dimensional (3D) in vitro skeletal muscle model to investigate steroid myopathy. By subjecting our bioengineered muscle tissues to dexamethasone treatment, we reproduced the molecular and functional aspects of this disease. Dexamethasone caused a substantial reduction in muscle force, myotube diameter and induced fatigue. We observed nuclear translocation of the glucocorticoid receptor (GCR) and activation of the ubiquitin-proteasome system within our model, suggesting their coordinated role in muscle atrophy. We then examined the therapeutic potential of taurine in our 3D model for steroid myopathy. Our findings revealed an upregulation of phosphorylated AKT by taurine, effectively countering the hyperactivation of the ubiquitin-proteasomal pathway. Importantly, we demonstrate that discontinuing corticosteroid treatment was insufficient to restore muscle mass and function. Taurine treatment, when administered concurrently with corticosteroids, notably enhanced contractile strength and protein turnover by upregulating the AKT-mTOR axis. Our model not only identifies a promising therapeutic target, but also suggests combinatorial treatment that may benefit individuals undergoing corticosteroid treatment or those diagnosed with adrenal tumors.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140760400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brianda A Hernández-Morán, Gillian Taylor, Álvaro Lorente-Macías, Andrew J Wood
{"title":"Degron tagging for rapid protein degradation in mice.","authors":"Brianda A Hernández-Morán, Gillian Taylor, Álvaro Lorente-Macías, Andrew J Wood","doi":"10.1242/dmm.050613","DOIUrl":"https://doi.org/10.1242/dmm.050613","url":null,"abstract":"Degron tagging allows proteins of interest to be rapidly degraded, in a reversible and tuneable manner, in response to a chemical stimulus. This provides numerous opportunities for understanding disease mechanisms, modelling therapeutic interventions and constructing synthetic gene networks. In recent years, many laboratories have applied degron tagging successfully in cultured mammalian cells, spurred by rapid advances in the fields of genome editing and targeted protein degradation. In this At a Glance article, we focus on recent efforts to apply degron tagging in mouse models, discussing the distinct set of challenges and opportunities posed by the in vivo environment.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140781411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}