Unconventional features of C9ORF72 expanded repeat in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are devastating neurodegenerative diseases that form two ends of a complex disease spectrum. Aggregation of RNA binding proteins is one of the hallmark pathologic features of ALS and FTDL and suggests perturbance of the RNA metabolism in their etiology. Recent identification of the disease-associated expansions of the intronic hexanucleotide repeat GGGGCC in the C9ORF72 gene further substantiates the case for RNA involvement. The expanded repeat, which has turned out to be the single most common genetic cause of ALS and FTLD, may enable the formation of complex DNA and RNA structures, changes in RNA transcription, and processing and formation of toxic RNA foci, which may sequester and inactivate RNA binding proteins. Additionally, the transcribed expanded repeat can undergo repeat-associated non-ATG-initiated translation resulting in accumulation of a series of dipeptide repeat proteins. Understanding the basis of the proposed mechanisms and shared pathways, as well as interactions with known key proteins such as TAR DNA-binding protein (TDP-43) are needed to clarify the pathology of ALS and/or FTLD, and make possible steps toward therapy development.
Department of Biotechnology, Jozef Stefan Institute, Ljubljana, Slovenia.
Sabina
S
Vatovec
Department of Biotechnology, Jozef Stefan Institute, Ljubljana, Slovenia; Biomedical Research Institute BRIS, Ljubljana, Slovenia.
Anja
A
Kovanda
Department of Biotechnology, Jozef Stefan Institute, Ljubljana, Slovenia; Biomedical Research Institute BRIS, Ljubljana, Slovenia. Electronic address: boris.rogelj@ijs.si.
Boris
B
Rogelj
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics*; D004268:DNA-Binding Proteins; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D066263:Protein Aggregation, Pathological; D011506:Proteins / Q000235:genetics*; D012313:RNA / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D012313:RNA
Amyotrophic lateral sclerosis; C9ORF72; Di-peptide repeats; Expanded G4C2 repeats; Frontotemporal lobar degeneration; G-quadruplex; I-motif; RAN translation; RNA foci; RNA toxicity; RNA-binding proteins; hnRNP