Mutant prion protein D202N associated with familial prion disease is retained in the endoplasmic reticulum and forms ‘curly’ intracellular aggregates

Transmissible Spongiform Encephalopathies are fatal neurodegenerative disorders of humans and animals that are familial, sporadic, and infectious in nature. Familial disorders of humans include Gerstmann–Straussler–Scheinker disease (GSS), familial Creutzfeldt–Jakob disease (CJD), and fatal familial insomnia, and result from point mutations in the prion protein gene. Although neurotoxicity in familial cases is believed to result from a spontaneous change in conformation of mutant prion protein (PrP) to the pathogenic PrP-scrapie (PrP^Sc) form, emerging evidence indicates otherwise. We have investigated the processing and metabolism of mutant PrP D202N (PrP^202N) in cell models to elucidate possible mechanisms of cytotoxicity. In this report, we demonstrate that PrP^202N expressed in human neuroblastoma cells fails to achieve a mature conformation following synthesis and accumulates in the endoplasmic reticulum as ‘curly’ aggregates. In addition, PrP^202N cells show increased sensitivity to free radicals, indicating that neuronal susceptibility to oxidative damage may account for the neurotoxicity observed in cases of GSS resulting from PrP D202N mutation. Yaping Gu and Susamma Verghese contributed equally.     

Genetic counseling for prion disease: Updates and best practices

Prion disease is a rare, fatal, and often rapidly progressive neurodegenerative disease. Ten to fifteen percent of cases are caused by autosomal dominant gain-of-function variants in the prion protein gene, PRNP. Rarity and phenotypic variability complicate diagnosis, often obscuring family history and leaving families unprepared for the genetic implications of an index case. Several recent developments inspire this update in best practices for prion disease genetic counseling. A new prion-detection assay has transformed symptomatic diagnosis. Meanwhile, penetrance, age of onset, and duration of illness have been systematically characterized across PRNP variants in a global cohort. Clinically, the traditional genotype–phenotype correlation has weakened over time, and the term genetic prion disease may now better serve providers than the historical subtypes Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker disease. Finally, in the age of genetically targeted therapies, clinical trials for prion disease are being envisaged, and healthy at-risk individuals may be best positioned to benefit. Such individuals need to be able to access clinical services for genetic counseling and testing. Thus, this update on the genetics of prion disease and best practices for genetic counseling for this disease aims to provide the information needed to expand genetic counseling services.     

云南地区卵巢癌患者的基因同源重组缺陷状态和BRCA1/2基因突变频率及其临床意义

目的：采用基于中国人群单核苷酸多态性位点开发的同源重组缺陷（HRD）检测工具评估云南地区卵巢癌患者的HRD状态和BRCA1/2基因突变频率并探讨其临床意义。方法：共纳入2021 年1月至2023 年5月间在云南省肿瘤医院收治的卵巢癌患者248 例，HRD状态采用基因组瘢痕评分法（GSS）（主要依据拷贝数的长度、类型、位置及基因组断片）或HRD评分法（杂合性缺失、端粒等位基因失衡及大片段移位等基因组不稳定事件的总和）进行评估，当组织样本的GSS≥50 分或HRD评分≥42 分者或检测到有害的BRCA1/2基因突变时HRD被定义为阳性。分析患者HRD状态与临床病理特征的关系。结果：248 名卵巢癌患者中70.97%的患者HRD呈阳性，其中BRCA1/2基因突变率为30.65%。Ⅲ~Ⅵ期、高级别浆液腺癌的卵巢癌患者具有更高的HRD阳性率（均P<0.01），HRD评分更高的患者其合并其他基因突变的频率也越高（P<0.05）。HRD状态与卵巢癌的病理类型、临床分期和其他基因突变均有关联（均P<0.01）。结论：云南地区卵巢癌患者HRD阳性率较高，HRD阳性的卵巢癌患者可以从聚ADP核糖聚合酶（PARP）抑制剂治疗中获得更大的收益。     

Role of methionine adenosyltransferase 2A and S-adenosylmethionine in mitogen-induced growth of human colon cancer cells

BACKGROUND & AIMS: Two genes (MAT1A and MAT2A) encode for methionine adenosyltransferase, an essential enzyme responsible for S-adenosylmethionine (SAMe) biosynthesis. MAT1A is expressed in liver, whereas MAT2A is widely distributed. In liver, increased MAT2A expression is associated with growth, while SAMe inhibits MAT2A expression and growth. The role of MAT2A in colon cancer in unknown. The aims of this study were to examine whether MAT2A expression and SAMe and its metabolite methylthioadenosine (MTA) can modulate growth of colon cancer cells. METHODS: Studies were conducted using resected colon cancer specimens, polyps from Min mice, and human colon cancer cell lines RKO and HT-29. MAT2A expression was measured by real-time polymerase chain reaction and cell growth by the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS: In 12 of 13 patients and all 9 polyps from Min mice, the MAT2A messenger RNA levels were 200%-340% of levels in adjacent normal tissues, respectively. Epidermal growth factor, insulin-like growth factor 1, and leptin increased growth and up-regulated MAT2A expression and MAT2A promoter activity in RKO and HT-29 cells. SAMe and MTA lowered the baseline expression of MAT2A and blocked the growth factor-mediated increase in MAT2A expression and growth in colon cancer cell lines. Importantly, the mitogenic effect of these growth factors was inhibited if MAT2A induction was prevented by RNA interference. SAMe and MTA supplementation in drinking water increased intestinal SAMe levels and lowered MAT2A expression. CONCLUSIONS: Similar to the liver, up-regulation of MAT2A also provides a growth advantage and SAMe and MTA can block mitogenic signaling in colon cancer cells.     

后路椎弓根内固定椎体间融合治疗腰椎滑脱症

[目的]探讨后路椎弓根内固定椎间融合术治疗腰椎滑脱症的方法和疗效。[方法]21例采用椎弓根螺钉(GSS)对腰椎滑脱提拉复位及固定,椎间植骨融合治疗腰椎滑脱症。[结果]术后随访8~24个月,根据侯树勋等所制定疗效评价标准,优17例,良2例,可1例,差1例,优良率为90.4%。20例达到骨性融合,总体融合率为95.2%,平均融合时间为3个月(2~4个月)。[结论]后路椎弓根内固定椎间植骨融合治疗腰椎滑脱症是一种成熟有效方法。     

通用型脊柱内固定系统在相邻两节段胸腰椎骨折中的运用

目的探讨相邻两节段胸腰椎骨折致伤机制、生物力学特点及运用通用型脊柱内固定系统（GSS）的稳定性及固定效果。方法对2002年1月～2008年12月共17例相邻两节段胸腰椎骨折采用GSS治疗进行回顾性分析。结果 17例均获得随访,固定后后凸角、椎体前缘高度较术前均明显改善,原突入椎管内骨块均基本复位或去除;随访时间9～70个月,平均28个月,术后常规卧床6w,椎体高度及后凸角无明显丢失,内固定无松动、断裂。固定前不全瘫的患者中,Frankel分级改善1～3级。结论 GSS用于相邻两节段胸腰椎骨折的内固定,具有安装简便、省时、固定牢靠等优点,结合早期常规卧床可获得良好的复位效果和临床疗效。     

GSS内固定撑开复位间接减压治疗胸腰椎爆裂骨折21例

胸腰椎椎体爆裂骨折是脊柱骨折中常见的类型。骨块突人、椎管狭窄,常伴有脊髓或马尾神经损伤。解剖复位、椎管减压并维持已获得的矫正是治疗的目标^[1]。本院自2004年6月～2007年8月共收治21例胸腰椎爆裂性骨折病例,采用后侧入路GSS撑开内固定椎板间融合术,     

GSS在腰椎管狭窄症伴退变性滑脱手术中的应用

目的 探讨通用型脊柱内固定系统（GSS）在腰椎管狭窄症伴退变性滑脱患者手术中的应用价值。方法 对16例腰椎管狭窄症伴退变性滑脱患者行后路全椎板减压、GSS内固定加植骨融合术，其中多节段腰椎管狭窄11例，单节段腰椎管狭窄5例；L4滑脱9例，L5滑脱7例；Meyerding分类Ⅰ度滑脱14例，Ⅱ度滑脱2例。结果术后随访6—24个月，平均14个月，采用Stauffer—Coventry下腰椎术后疗效评定标准，优良率为88％，植骨融合率为100％，GSS无松动退出及断裂现象。结论在腰椎管狭窄症伴退变性滑脱后路全椎板减压术中，GSS系统可提供滑脱复位，恢复椎间隙高度及腰椎生理前凸，术后即刻稳定，植骨融合率高，是一种安全有效、操作简便的内固定系统。