Role of the C9ORF72 Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.
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 non-C9ORF72 expansion-related ALS, FTD, and other neurodegenerative diseases.
['Hao|Zongbing|Z|', 'Wang|Rui|R|', 'Ren|Haigang|H|http://orcid.org/0000-0001-8844-4754', 'Wang|Guanghui|G|http://orcid.org/0000-0001-8551-6468']
D000690:Amyotrophic Lateral Sclerosis D000818:Animals D000073885:C9orf72 Protein D042622:DNA Repeat Expansion D057180:Frontotemporal Dementia D006801:Humans D051379:Mice D008822:Mice, Transgenic D011506:Proteins
C9ORF72 Amyotrophic lateral sclerosis Frontotemporal dementia Dipeptide repeat proteins Pathological inclusions