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ALS與ALS/FTD病人群體的Ubiquilin神經病理學與C9ORF72 六核甘酸重複頻率研究


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ALSALS/FTD病人群體的Ubiquilin神經病理學與C9ORF72 六核甘酸重複頻率研究

 

  

譯者/郭書瑋/西北大學博士生

簡介: C9ORF72異常與Ubiquilin2蛋白是今年最受ALS研究者矚目的突破性發展。這篇poster提供了臨床上兩者間潛在的關聯性,同時強調了Ubiquilin2ALS病理學上的顯著性。兩者之間的關聯性與交互作用值得進一步探討。

 

翻譯: 在一部分的ALS病人身上會共伴有FTD(額顳葉退化症)。染色體上的C9ORD72位置異常(即六核甘酸重複)在此群體中發生頻率特別高,此異常也發生在相當的比例的家族性與偶發性ALS病患身上。然而更進一步的疾病發生機轉(尤其在細胞分子生物學層次)仍然相當不清楚。

 

1807例無其他已知基因突變的ALS患者中, 281例帶有C9ORF72異常 。此異常在家族性ALS與家族性ALS/FTD病人身上的發生頻率顯著的高於偶發性ALS與偶發性ALS/FTD病人。

 

更為重要的是,經過免疫組織學檢查以及共軛焦顯微鏡檢,大部分的C9ORF72  異常案例都發現Ubiquilin2蛋白的異常堆積。有趣的是之前廣受矚目的TDP43FUS蛋白則未檢出異常。由此,似乎C9ORF72異常(基因層次)Ubiquilin2蛋白異常(蛋白質層次)存在一定的關聯性,值得進一步探討。是否C9ORF72異常與Ubiquilin2蛋白異常有直接的交互作用/關聯性目前不得而知。

 

此研究突顯出Ubiquilin2蛋白異常的廣泛存在,以及與C9ORF72異常的高共伴率。同時更進一步強調蛋白質代謝/降解相關途徑在神經退化性疾病(例如FTD以及阿茲海默症)尤其是ALS上的重要性。

 

原文如下

 

P107 UBIQUILIN NEUROPATHOLOGY AND FREQUENCY OF C9ORF72 HEXANUCLEOTIDE EXPANSION IN A LARGE COHORT OF ALS AND ALS/FTD PATIENTS 

 

Authors: YAN et al.

 

Institutes: Northwestern University Feinberg School of Medicine, Chicago, IL, USA   

 

Background:  C9ORF72-hexanucleotide repeat (GGGGCC) n was found to be expanded in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTD). Incidence of expansion was reported in relative small sample sizes, varying from 22.5% to 46.4% in FALS, 4.1% to 21% in SALS, and 10.4% to 50.6% in FALS/ FTD. The pathogenic mechanism of the C9ORF72-linked ALS/FTD remains largely unknown.  

 

Objectives:  To evaluate the frequency of C9ORF72-hexanucleotide expansion in a large cohort of ALS and ALS/ FTD of North America patients and to characterize the C9ORF72-related neuropathology.  

 

Methods:  A cohort of 1,807 cases without known gene mutations, including 420 FALS, 1235 SALS, 134 FALS/ FTD, 18 SALS/FTD was analyzed. In addition, a total of 704 control subjection was also included. Expansion of C9ORF72-hexanucleotide was determined by repeat-primed PCR and further confirmed by Sanger sequencing in 281 cases. Samples with large number of repeats were also analyzed by Southern blot. Immunohistochemistry and confocal microscopy were performed on hippocampal sections from patients with C9ORF72 mutations.  

 

Results: The frequencies of C9ORF72-hexanucleotide expansion were 43.8% in FALS, 4.5% in SALS, 61.2% in FALS/FTD, and 5.6% in SALS/FTD, respectively. The expansion frequency in the whole FALS population was 29.1%. No expansion was found in the 704 controls. The allele (GGGGCC)2 represented the most frequent allele in the control cohort, which accounted for 50.4% of the total alleles. Rare alleles with limited repeat expansion were observed in controls ((GGGGCC)21, n=1; (GGGGCC)20, n=3)), but no repeat expansion over 21 was observed. The ubiquilin2-positive aggregates in the molecular layer of the dentate gyrus and CA1-CA4, which were also ubiquitin and p62-positive, but TDP43- and FUS-negative, appeared to be a characteristic pathology in the C9ORF72- linked cases.  

 

Discussion: The hexanucleotide expansions in the intron of C9ORF72 represent the most frequent mutations identified to date in familial ALS and ALS/FTD cases. The presence of the ubiquilin2-positive aggregates in the molecular layer of the dentate gyrus and CA1-CA4, which were ubiquitin- and p62-positive, but TDP43- and FUS-negative, suggests that ubiquilinopathy is a specific and common pathological hallmark in both ALS and ALS/FTD. Our data indicate that protein/organelle degradation defect may be a common mechanism underlying ALS and FTD.  

 

Acknowledgements: Les Turner ALS Foundation, NINDS, Blazeman Foundation.

 

DOI: 10.3109/17482968.2012.721231/203

 

文章出處

 

2012 ALS/MND International Symposium

Poster Abstract

 

Theme 5 Genetics

 

P107 UBIQUILIN NEUROPATHOLOGY AND FREQUENCY OF C9ORF72 HEXANUCLEOTIDE EXPANSION IN A LARGE COHORT OF ALS AND ALS/FTD PATIENTS

 

J Yan, N Siddique, Z Zhai,  S Ajroud-Driss, R Flint, J Allen,  JG Zheng, Y Yang, W Chen,  EH Bigio, H-X Deng, T Siddique

 

(本文出自漸凍人協會會訊2013年1月第133~134期)

 
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