Rare diseases (Austin, Tex.)最新文献_第3页

Pigmentation-based insertional mutagenesis is a simple and potent screening approach for identifying neurocristopathy-associated genes in mice. 基于色素的插入突变是一种简单而有效的筛选方法，用于鉴定小鼠神经嵴病变相关基因。

Rare diseases (Austin, Tex.) Pub Date : 2016-03-03 eCollection Date: 2016-01-01 DOI: 10.1080/21675511.2016.1156287

Nicolas Pilon

引用次数: 15

The conditional KO approach: Cre/Lox technology in human neurons. 条件KO方法:人神经元的Cre/Lox技术。

Rare diseases (Austin, Tex.) Pub Date : 2016-02-18 eCollection Date: 2016-01-01 DOI: 10.1080/21675511.2015.1131884

Christopher Patzke, Thomas C Südhof

引用次数: 10

Dystrophin: The dead calm of a dogma. 肌营养不良症：死气沉沉的教条

Rare diseases (Austin, Tex.) Pub Date : 2016-02-18 eCollection Date: 2016-01-01 DOI: 10.1080/21675511.2016.1153777

Dariusz C Górecki

{"title":"Dystrophin: The dead calm of a dogma.","authors":"Dariusz C Górecki","doi":"10.1080/21675511.2016.1153777","DOIUrl":"10.1080/21675511.2016.1153777","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease leading to severe disability and death of young men. Current interventions are palliative as no treatment improves the long-term outcome. Therefore, new therapeutic modalities with translational potential are urgently needed and abnormalities downstream from the absence of dystrophin are realistic targets. It has been shown that DMD mutations alter extracellular ATP (eATP) signaling via P2RX7 purinoceptor upregulation, which leads to autophagic death of dystrophic muscle cells. Furthermore, the eATP-P2RX7 axis contributes to DMD pathology by stimulating harmful inflammatory responses. We demonstrated recently that genetic ablation or pharmacological inhibition of P2RX7 in the mdx mouse model of DMD produced functional attenuation of both muscle and non-muscle symptoms, establishing this receptor as an attractive therapeutic target. Central to the argument presented here, this purinergic phenotype affects dystrophic myoblasts. Muscle cells were believed not to be affected at this stage of differentiation, as they do not produce detectable dystrophin protein. Our findings contradict the central hypothesis stating that aberrant dystrophin expression is inconsequential in myoblasts and the DMD pathology results from effects such as sarcolemma fragility, due to the absence of dystrophin, in differentiated myofibres. However, we discuss here the evidence that, already in myogenic cells, DMD mutations produce a plethora of abnormalities, including in cell proliferation, differentiation, energy metabolism, Ca(2+) homeostasis and death, leading to impaired muscle regeneration. We hope that this discussion may bring to light further results that will help re-evaluating the established belief. Clearly, understanding how DMD mutations alter such a range of functions in myogenic cells is vital for developing effective therapies. ","PeriodicalId":74639,"journal":{"name":"Rare diseases (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/8f/c6/krad-04-01-1153777.PMC4838315.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34451713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Problems and solutions for the analysis of somatic CAG repeat expansion and their relationship to Huntington's disease toxicity. 体细胞CAG重复扩增及其与亨廷顿病毒性关系分析的问题与解决方法

Rare diseases (Austin, Tex.) Pub Date : 2016-02-18 eCollection Date: 2016-01-01 DOI: 10.1080/21675511.2015.1131885

Helen Budworth, Cynthia T McMurray

{"title":"Problems and solutions for the analysis of somatic CAG repeat expansion and their relationship to Huntington's disease toxicity.","authors":"Helen Budworth, Cynthia T McMurray","doi":"10.1080/21675511.2015.1131885","DOIUrl":"https://doi.org/10.1080/21675511.2015.1131885","url":null,"abstract":"Huntington's Disease is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. Whether somatic expansion contributed to toxicity was unknown. From extensive work from multiple laboratories, it has been made clear that toxicity depended on length of the inherited allele, but whether preventing or delaying somatic repeat expansion in vivo would be beneficial was unknown, since the inherited disease allele was still expressed. In Budworth et al., we provided definitive evidence that suppressing the somatic expansion in mice substantially delays disease onset in littermates that inherit the same disease-length allele. This key discovery opens the door for therapeutic approaches targeted at stopping or shortening the CAG tract during life. The analysis was difficult and, at times, non-standard. Here, we take the opportunity to discuss the challenges, the analytical solutions, and to address some controversial issues with respect to expansion biology. ","PeriodicalId":74639,"journal":{"name":"Rare diseases (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21675511.2015.1131885","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34451711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7

Mitochondrial dysfunction and defects in lipid homeostasis as therapeutic targets in neurodegeneration with brain iron accumulation. 线粒体功能障碍和脂质稳态缺陷作为脑铁积累性神经变性的治疗靶点。

Rare diseases (Austin, Tex.) Pub Date : 2016-01-25 eCollection Date: 2016-01-01 DOI: 10.1080/21675511.2015.1128616

Kerri J Kinghorn, Jorge Iván Castillo-Quan

{"title":"Mitochondrial dysfunction and defects in lipid homeostasis as therapeutic targets in neurodegeneration with brain iron accumulation.","authors":"Kerri J Kinghorn, Jorge Iván Castillo-Quan","doi":"10.1080/21675511.2015.1128616","DOIUrl":"https://doi.org/10.1080/21675511.2015.1128616","url":null,"abstract":"The PLA2G6 gene encodes a group VIA calcium independent phospholipase A2 (iPLA2β), which hydrolyses glycerophospholipids to release fatty acids and lysophospholipids. Mutations in PLA2G6 are associated with a number of neurodegenerative disorders including neurodegeneration with brain iron accumulation (NBIA), infantile neuroaxonal dystrophy (INAD), and dystonia parkinsonism, collectively known as PLA2G6-associated neurodegeneration (PLAN). Recently Kinghorn et al. demonstrated in Drosophila and PLA2G6 mutant fibroblasts that loss of normal PLA2G6 activity is associated with mitochondrial dysfunction and mitochondrial lipid peroxidation. Furthermore, they were able to show the beneficial effects of deuterated polyunsaturated fatty acids (D-PUFAs), which reduce lipid peroxidation. D-PUFAs were able to rescue the locomotor deficits of flies lacking the fly ortholog of PLA2G6 (iPLA2-VIA), as well as the mitochondrial abnormalities in PLA2G6 mutant fibroblasts. This work demonstrated that the iPLA2-VIA knockout fly is a useful organism to dissect the mechanisms of pathogenesis of PLAN, and that further investigation is required to determine the therapeutic potential of D-PUFAs in patients with PLA2G6 mutations. The fruit fly has also been used to study some of the other genetic causes of NBIA, and here we also describe what is known about the mechanisms of pathogenesis of these NBIA variants. Mitochondrial dysfunction, defects in lipid metabolism, as well as defective Coenzyme A (CoA) biosynthesis, have all been implicated in some genetic forms of NBIA, including PANK2, CoASY, C12orf19 and FA2H. ","PeriodicalId":74639,"journal":{"name":"Rare diseases (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21675511.2015.1128616","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34451707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 15

Beyond multiple mechanisms and a unique drug: Defective autophagy as pivotal player in cerebral cavernous malformation pathogenesis and implications for targeted therapies. 超越多种机制和一种独特的药物:有缺陷的自噬在脑海绵体畸形的发病机制和靶向治疗中的关键作用。

Rare diseases (Austin, Tex.) Pub Date : 2016-01-25 eCollection Date: 2016-01-01 DOI: 10.1080/21675511.2016.1142640

Saverio Marchi, Eliana Trapani, Mariangela Corricelli, Luca Goitre, Paolo Pinton, Saverio Francesco Retta

{"title":"Beyond multiple mechanisms and a unique drug: Defective autophagy as pivotal player in cerebral cavernous malformation pathogenesis and implications for targeted therapies.","authors":"Saverio Marchi, Eliana Trapani, Mariangela Corricelli, Luca Goitre, Paolo Pinton, Saverio Francesco Retta","doi":"10.1080/21675511.2016.1142640","DOIUrl":"https://doi.org/10.1080/21675511.2016.1142640","url":null,"abstract":"Cerebral Cavernous Malformation (CCM) is a major cerebrovascular disease of proven genetic origin affecting 0.3-0.5% of the general population. It is characterized by abnormally enlarged and leaky capillaries, which predispose to seizures, focal neurological deficits and intracerebral hemorrhage. Causative loss-of-function mutations have been identified in 3 genes, KRIT1 (CCM1), CCM2 and PDCD10 (CCM3). While providing new options for the development of pharmacological therapies, recent advances in knowledge of the functions of these genes have clearly indicated that they exert pleiotropic effects on several biological pathways. Recently, we found that defective autophagy is a common feature of loss-of-function mutations of the 3 known CCM genes, and underlies major phenotypic signatures of CCM disease, including endothelial-to-mesenchymal transition and enhanced ROS production, suggesting a unifying pathogenetic mechanism and reconciling the distinct therapeutic approaches proposed so far. In this invited review, we discuss autophagy as a possible unifying mechanism in CCM disease pathogenesis, and new perspectives and avenues of research for disease prevention and treatment, including novel potential drug repurposing and combination strategies, and identification of genetic risk factors as basis for development of personalized medicine approaches. ","PeriodicalId":74639,"journal":{"name":"Rare diseases (Austin, Tex.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21675511.2016.1142640","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34451712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 26

Listen to your gut: Using adhesion to shape the surface of functionally diverse epithelia 倾听你的肠道:利用粘连来塑造功能多样的上皮细胞表面

Rare diseases (Austin, Tex.) Pub Date : 2016-01-01 DOI: 10.1080/21675511.2016.1220469

M. Tyska

引用次数: 0

Staufen1s role as a splicing factor and a disease modifier in Myotonic Dystrophy Type I staufen1在I型肌强直性营养不良中作为剪接因子和疾病调节剂的作用

Rare diseases (Austin, Tex.) Pub Date : 2016-01-01 DOI: 10.1080/21675511.2016.1225644

Emma Bondy-Chorney, Tara E. Crawford Parks, A. Ravel-Chapuis, B. Jasmin, J. Côté

引用次数: 5

Canine models of human rare disorders 人类罕见疾病的犬类模型

Rare diseases (Austin, Tex.) Pub Date : 2016-01-01 DOI: 10.1080/21675511.2016.1241362

M. Hytönen, H. Lohi

引用次数: 48

Molecular mechanisms underlying Spinocerebellar Ataxia 17 (SCA17) pathogenesis 脊髓小脑性共济失调17 (SCA17)发病机制的分子机制

Rare diseases (Austin, Tex.) Pub Date : 2016-01-01 DOI: 10.1080/21675511.2016.1223580

Su Yang, Xiao-Jiang Li, Shihua Li

引用次数: 21