In-depth clinico-pathological examination of RNA foci in a large cohort of C9ORF72 expansion carriers

Autor: Anthony Lucido, Linda Rousseau, Xue Wang, Mariely DeJesus-Hernandez, Jan de Boer, Ni Cole A. Finch, Ronald C. Petersen, Aliaksei Vasilevich, Tania F. Gendron, Keith A. Josephs, Neill R. Graff-Radford, Marka van Blitterswijk, Yan W. Asmann, Jeannie Chew, Kevin F. Bieniek, Joseph E. Parisi, Leonard Petrucelli, Kevin B. Boylan, Michael G. Heckman, Dennis W. Dickson, David S. Knopman, Rachael Weesner, Meeia Parsons, Melissa E. Murray, Rosa Rademakers, Bradley F. Boeve
Přispěvatelé: RS: MERLN - Cell Biology - Inspired Tissue Engineering (CBITE), CBITE
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
Cerebellum
Pathology
Cell
TOXICITY
DIPEPTIDE-REPEAT PROTEINS
Cohort Studies
0302 clinical medicine
C9orf72
Sense (molecular biology)
ALS/FTD
Neurons
DNA Repeat Expansion
Neurodegeneration
Brain
Middle Aged
Antisense RNA
medicine.anatomical_structure
Female
NEURONAL LOSS
Frontotemporal dementia
medicine.medical_specialty
C9ORF72
Chromosome 9
Biology
Pathology and Forensic Medicine
03 medical and health sciences
Cellular and Molecular Neuroscience
medicine
Humans
RNA
Antisense
RNA
Messenger
Motor neuron disease
BAC TRANSGENIC MICE
Aged
Original Paper
Analysis of Variance
Electronic Data Processing
FRONTOTEMPORAL LOBAR DEGENERATION
HEXANUCLEOTIDE REPEAT
C9orf72 Protein
ANTISENSE TRANSCRIPTS
RNA foci
RNA
medicine.disease
Amyotrophic lateral sclerosis
030104 developmental biology
PATHOLOGICAL FEATURES
Neurology (clinical)
Human medicine
ALS
030217 neurology & neurosurgery
Zdroj: Acta Neuropathologica
Acta Neuropathologica, 134(2), 255-269. Springer, Cham
Acta neuropathologica
ISSN: 0001-6322
Popis: A growing body of evidence suggests that a loss of chromosome 9 open reading frame 72 (C9ORF72) expression, formation of dipeptide-repeat proteins, and generation of RNA foci contribute to disease pathogenesis in amyotrophic lateral sclerosis and frontotemporal dementia. Although the levels of C9ORF72 transcripts and dipeptide-repeat proteins have already been examined thoroughly, much remains unknown about the role of RNA foci in C9ORF72-linked diseases. As such, we performed a comprehensive RNA foci study in an extensive pathological cohort of C9ORF72 expansion carriers (n = 63). We evaluated two brain regions using a newly developed computer-automated pipeline allowing recognition of cell nuclei and RNA foci (sense and antisense) supplemented by manual counting. In the frontal cortex, the percentage of cells with sense or antisense RNA foci was 26 or 12%, respectively. In the cerebellum, 23% of granule cells contained sense RNA foci and 1% antisense RNA foci. Interestingly, the highest percentage of cells with RNA foci was observed in cerebellar Purkinje cells (~70%). In general, more cells contained sense RNA foci than antisense RNA foci; however, when antisense RNA foci were present, they were usually more abundant. We also observed that an increase in the percentage of cells with antisense RNA foci was associated with a delayed age at onset in the frontal cortex (r = 0.43, p = 0.003), whereas no other associations with clinico-pathological features were seen. Importantly, our large-scale study is the first to provide conclusive evidence that RNA foci are not the determining factor of the clinico-pathological variability observed in C9ORF72 expansion carriers and it emphasizes that the distribution of RNA foci does not follow the pattern of neurodegeneration, stressing the complex interplay between different aspects of C9ORF72-related diseases. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1725-7) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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