Key Points
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Since its discovery as the most common genetic abnormality in familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), researchers have sought to understand the pathophysiology that results from the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide expansion. Several pathways have been proposed to contribute.
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The nucleotide expansion may disrupt transcription, promoter activation and epigenetic regulation and may therefore drive a loss of C9orf72 function.
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A body of evidence suggests that cellular dysfunction results from toxicity that occurs downstream of the nucleotide repeat.
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There are several types of pathology associated with the nucleotide expansion that may drive this toxicity, including RNA foci, dipeptide repeat aggregates and nuclear pathology.
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Nucleocytoplasmic transport defects are a key contributor to C9orf72-driven pathophysiology. Studies of human brains, induced pluripotent stem cell-derived neurons, flies and yeast models, converge to suggest that nuclear export and import are defective in cells carrying the mutation.
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Several therapeutic strategies are being explored. For example, antisense oligonucleotides and small molecules may mitigate toxicity caused by the C9orf72 nucleotide repeat expansion.
Abstract
A nucleotide repeat expansion (NRE) within the chromosome 9 open reading frame 72 (C9orf72) gene was the first of this type of mutation to be linked to multiple neurological conditions, including amyotrophic lateral sclerosis and frontotemporal dementia. The pathogenic mechanisms through which the C9orf72 NRE contributes to these disorders include loss of C9orf72 function and gain-of-function mechanisms of C9orf72 driven by toxic RNA and protein species encoded by the NRE. These mechanisms have been linked to several cellular defects — including nucleocytoplasmic trafficking deficits and nuclear stress — that have been observed in both patients and animal models.
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Acknowledgements
The authors thank L. Ranum, A. Gitler, L. Petrucelli, P. Taylor, D. Cleveland, F. Bennet, F. Rigo, J. Wang, P. Wong and T. Lloyd for discussions that helped provide a foundation for this Review. Financial support was provided from the following institutes: the National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS); Target ALS; the Muscular Dystrophy Association; the Robert Packard Center for ALS Research; the Live Like Lou at the Pittsburgh Foundation; and the Brain Institute at the University of Pittsburgh School of Medicine, USA.
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Supplementary information
Supplementary information S1 (table)
Mechanisms of C9orf72 Pathophysiology (PDF 156 kb)
Supplementary information S2 (table)
Author-provided unique (G4C2)n RNA•protein interactors lists* (XLSX 44 kb)
Glossary
- GDP–GTP nucleotide exchange factor
-
(GEF). A protein that functions to stimulate the release of guanosine diphosphate (GDP) from a GTPase to allow subsequent binding of the guanosine triphosphate (GTP) to the active site.
- Epigenetic silencing
-
Covalent DNA or histone modifications, such as DNA or histone methylation, that act to repress or silence a genomic region by reducing access of the transcriptional machinery to the DNA.
- Polymerase processivity
-
A relative measure of the functional efficiency and rate of polymerase to process (replicate or transcribe) nucleic acid information.
- Bidirectional transcription
-
Transcription that occurs simultaneously on both the positive and the negative strands of DNA, where the direction of RNA polymerase progression along each strand is either convergent or divergent.
- Haplotype
-
A combination of alleles at different loci in the genome that tend to be inherited together because they show high linkage disequilibrium (often because they are physically close).
- Induced pluripotent stem cells
-
(iPSCs). Cells that are created from differentiated cell types — for example, fibroblasts — that are reprogrammed by a cocktail of transcription factors (or other approaches) back to a pluripotent state. These cells can then be differentiated into cells of distinct lineages — for example, neurons.
- R loops
-
A nucleic acid structure that occurs when a single strand of RNA invades a double-stranded DNA, forming an RNA:DNA hybrid that is stabilized through Watson–Crick base pairs, and leaves a displaced single-stranded DNA molecule.
- dsDNA melting
-
The separation of base-paired DNA strands through the disruption of Watson–Crick pairing by physical or thermodynamic means.
- Interactomes
-
Sets of physical interactions occurring between two or more components.
- G-quadruplex
-
A structure composed of G-quartets, four planar guanine molecules that are stabilized by Hoogsteen base pairing, that are stacked on top of each other and stabilized by a central cation and π-stacking interactions between the G-quartets.
- Hairpin
-
A nucleic acid molecule that contains a stem region, which can be composed of complimentary base pairing and be interspersed with single-stranded or loop elements, and contains a tight looped region (hairpin turn) at the end of the base-paired stem region.
- Repeat-associated non-ATG-dependent translation
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(RANT). The non-canonical translation of a repetitive RNA sequence initiated by an AUG start codon.
- Nucleocytoplasmic trafficking
-
The bidirectional protein transport between the cytoplasm and the nuclear matrix through the nuclear pore complex.
- Genetic modifier
-
A genetic variation in (cis) or outside (trans) a gene or genetic locus that alters the phenotypic expression of the gene.
- CRISPR/Cas technology
-
The essential components of the bacterial adaptive immunity, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated (Cas) genes, that are currently being utilized and developed for precise editing, regulating and targeting of genes in model systems and organisms.
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Haeusler, A., Donnelly, C. & Rothstein, J. The expanding biology of the C9orf72 nucleotide repeat expansion in neurodegenerative disease. Nat Rev Neurosci 17, 383–395 (2016). https://doi.org/10.1038/nrn.2016.38
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DOI: https://doi.org/10.1038/nrn.2016.38
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