Role of the C9ORF72 Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
- PDF / 1,097,897 Bytes
- 14 Pages / 595.276 x 790.866 pts Page_size
- 2 Downloads / 171 Views
www.neurosci.cn www.springer.com/12264
REVIEW
Role of the C9ORF72 Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Zongbing Hao1 • Rui Wang1 • Haigang Ren1
•
Guanghui Wang1
Received: 19 January 2020 / Accepted: 30 April 2020 Ó Shanghai Institutes for Biological Sciences, CAS 2020
Abstract Since the discovery of the C9ORF72 gene in 2011, great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms; it is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS patients with C9ORF72 expansion show heterogeneous symptoms. Those who are C9ORF72 expansion carriers have shorter survival after disease onset than non-C9ORF72 expansion patients. Pathological and clinical features of C9ORF72 patients have been well mimicked via several models, including induced pluripotent stem cell-derived neurons and transgenic mice that were embedded with bacterial artificial chromosome construct and that overexpressing dipeptide repeat proteins. The mechanisms implicated in C9ORF72 pathology include DNA damage, changes of RNA metabolism, alteration of phase separation, and impairment of nucleocytoplasmic transport, which may underlie C9ORF72 expansion-related ALS/FTD and provide insight into nonC9ORF72 expansion-related ALS, FTD, and other neurodegenerative diseases. Keywords Amyotrophic lateral sclerosis Frontotemporal dementia C9ORF72 Dipeptide repeat proteins Pathological inclusions
& Guanghui Wang [email protected] 1
Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
Introduction Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a deficiency of upper and lower motor neurons in the motor cortex and lumbar spinal cord, respectively [1]. Frontotemporal dementia (FTD) is a devastating disease that mainly involves the frontal and temporal lobes [2]. A GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the intron of the C9ORF72 gene was identified in 2011 and is the most common genetic cause of both ALS and FTD [3–5]. Tens to thousands of G4C2 repeats have been identified in carriers and patients with the C9ORF72-related ALS and FTD (c9ALS/FTD) mutation, while only *30 repeats occur in normal individuals [3, 4]. The HRE can be further transcribed and translated into sense and antisense RNAs, as well as dipeptide repeat proteins (DPRs) that include poly-GA, poly-GP, poly-GR, poly-PA, and poly-PR [6–12]. The underlying mechanisms of c9ALS/FTD can be classified into three prototypes (Fig. 1): (1) loss-of-function of the C9ORF72 protein [13–17]; (2) formation of sense and antisense RNA foci in the nucleus [18–20]; and (3) gain-of-function caused by repeat-associated non-ATGinitiated translation of DPRs [21–24]. In recent years, several studies have implicated C9ORF72 in cellular protein
Data Loading...
