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Structure and Dynamics of DNA and RNA Double Helices Obtained from the GGGGCC and CCCCGG Hexanucleotide Repeats That Are the Hallmark of C9FTD/ALS Diseases.

ABSTRACT: A (GGGGCC) hexanucleotide repeat (HR) expansion in the C9ORF72 gene, and its associated antisense (CCCCGG) expansion, are considered the major cause behind frontotemporal dementia and amyotrophic lateral sclerosis. We have performed molecular dynamics simulations to characterize the conformation and dynamics of the 12 duplexes that result from the three different reading frames in sense and antisense HRs for both DNA and RNA. These duplexes display atypical structures relevant not only for a molecular level understanding of these diseases but also for enlarging the repertoire of nucleic-acid structural motifs. G-rich helices share common features. The inner G-G mismatches stay inside the helix in Gsyn-Ganti conformations and form two hydrogen bonds (HBs) between the Watson-Crick edge of Ganti and the Hoogsteen edge of Gsyn. In addition, Gsyn in RNA forms a base-phosphate HB. Inner G-G mismatches cause local unwinding of the helix. G-rich double helices are more stable than C-rich helices due to better stacking and HBs of G-G mismatches. C-rich helix conformations vary wildly. C mismatches flip out of the helix in DNA but not in RNA. Least (most) stable C-rich RNA and DNA helices have single (double) mismatches separated by two (four) Watson-Crick basepairs. The most stable DNA structure displays an "e-motif" where mismatched bases flip toward the minor groove and point in the 5' direction. There are two RNA conformations, where the orientation and HB pattern of the mismatches is coupled to bending of the helix.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5423440 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Structure and Dynamics of DNA and RNA Double Helices Obtained from the GGGGCC and CCCCGG Hexanucleotide Repeats That Are the Hallmark of C9FTD/ALS Diseases.

Zhang Yuan Y Roland Christopher C Sagui Celeste C

ACS chemical neuroscience 20161219 3

A (GGGGCC) hexanucleotide repeat (HR) expansion in the C9ORF72 gene, and its associated antisense (CCCCGG) expansion, are considered the major cause behind frontotemporal dementia and amyotrophic lateral sclerosis. We have performed molecular dynamics simulations to characterize the conformation and dynamics of the 12 duplexes that result from the three different reading frames in sense and antisense HRs for both DNA and RNA. These duplexes display atypical structures relevant not only for a mol ...[more]

PMID: 27933757

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Project description:Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a disease spectrum associated with TDP-43 pathology. Strong evidence supporting this is the existence of kindreds with family members affected by FTD, ALS or mixed features of FTD and ALS, referred to as FTD-MND. Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. Discovery of the mutation defines c9FTD/ALS. Prior to discovery of mutations in C9ORF72, it was assumed that TDP-43 pathology in c9FTD/ALS was uniform. In this study, we examined the neuropathology and clinical features of 20 cases of c9FTD/ALS from a brain bank for neurodegenerative disorders. Included are six patients clinically diagnosed with ALS, eight FTD, one FTD-MND and four Alzheimer-type dementia. Clinical information was unavailable for one patient. Pathologically, the cases all had TDP-43 pathology, but there were three major pathologic groups: ALS, FTLD-MND and FTLD-TDP. The ALS cases were morphologically similar to typical sporadic ALS with almost no extramotor TDP-43 pathology; all had oligodendroglial cytoplasmic inclusions. The FTLD-MND showed predominantly Mackenzie Type 3 TDP-43 pathology, and all had ALS-like pathology in motor neurons, but more extensive extramotor pathology, with oligodendroglial cytoplasmic inclusions and infrequent hippocampal sclerosis. The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. FTLD-TDP patients were older and some were thought to have Alzheimer-type dementia. In addition to the FTD and ALS clinical presentations, the present study shows that c9FTD/ALS can have other presentations, possibly related to age of onset and the presence of hippocampal sclerosis. Moreover, there is pathologic heterogeneity not only between ALS and FTLD, but also within the FTLD group. Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72.

Dataset Information

Structure and Dynamics of DNA and RNA Double Helices Obtained from the GGGGCC and CCCCGG Hexanucleotide Repeats That Are the Hallmark of C9FTD/ALS Diseases.

Publications

Structure and Dynamics of DNA and RNA Double Helices Obtained from the GGGGCC and CCCCGG Hexanucleotide Repeats That Are the Hallmark of C9FTD/ALS Diseases.

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