Journal of Shanghai Jiao Tong University (Medical Science) >

2022 , Vol. 42 >Issue 10: 1482 - 1489

DOI: https://doi.org/10.3969/j.issn.1674-8115.2022.10.015

Review

Initiation and regulatory mechanism of C9ORF72 (G4C2)n RAN translation

  • Yiyuan FENG ,
  • Zhongyun XU ,
  • Lin DING ,
  • Yafu YIN ,
  • Hui WANG ,
  • Weiwei CHENG
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  • 1.Department of Nuclear Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
    2.Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
CHENG Weiwei, E-mail: wcheng37@outlook.com.

Received date: 2022-01-10

  Accepted date: 2022-06-14

  Online published: 2022-12-02

Supported by

National Natural Science Foundation of China(81901162);Shanghai Rising-Star Program(20QA1406300)

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Abstract

As one of the main pathogenic mechanisms of the microsatellite repeat expansion diseases, the repeats from the abnormal DNA expansion produce toxic proteins through repeat-associated non-AUG (RAN) translation, which can causes neuronal death. Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons, while frontotemporal dementia (FTD) is a less common early-onset dementia compared to Alzheimer′s disease. C9ORF72 (G4C2)n abnormal expansion is the most common cause of ALS/FTD. Three mechanisms have been proposed for abnormal expansion of (G4C2)n in C9ORF72: ① The C9ORF72 loss-of-function results from the transcription suppression of C9ORF72 caused by the abnormal expansion of (G4C2)n in C9ORF72. ② The RNA foci from the abnormal expansion of (G4C2)n in C9ORF72, which bind to multiple RNA binding protein (RBP), lead to the dysfunction of these RBP. ③ The repeats from the abnormal expansion of (G4C2)n in C9ORF72 undergoing RAN translation produce the dipeptide repeat proteins (DPRs), which results in their toxic gain-of-function. Many studies have evidenced that RAN translation plays a pivotal role in disease progression. While a lot of studies focus on the pathologic mechanism of DPRs, the initiation and regulation mechanism of C9ORF72 (G4C2)n RAN translation is unknown and severely hinders the application of RAN translation as the therapeutic target in ALS/FTD. This review summarizes the most updated literatures on initiation and regulation mechanism of C9ORF72 (G4C2)n RAN translation and discusses the feasibility of reducing cellular toxicity and increasing neuron survival by targeting C9ORF72 (G4C2)n RAN translation.

Key words： C9ORF72 mutation; abnormal expansion of GGGGCC repeat; repeat associated non-AUG (RAN) translation; amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD)

Cite this article

Yiyuan FENG , Zhongyun XU , Lin DING , Yafu YIN , Hui WANG , Weiwei CHENG . Initiation and regulatory mechanism of C9ORF72 (G4C2)n RAN translation[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022 , 42(10) : 1482 -1489 . DOI: 10.3969/j.issn.1674-8115.2022.10.015

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