PERSPECTIVES Disease Mechanisms of C9ORF72 Repeat Expansions

G4C2 repeat expansions within the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These bidirectionally transcribed expansions lead to (1) the accumulation of sense G4C2 and antisense G2C4 repeat-containing RNA, (2) the production of proteins of repeating dipeptides through unconventional translation of these transcripts, and (3) decreased C9ORF72 mRNA and protein expression. Consequently, there is ample opportunity for the C9ORF72 mutation to give rise to a spectrum of clinical manifestations, ranging from muscle weakness and atrophy to changes in behavior and cognition. It is thus somewhat surprising that investigations of these three seemingly disparate events often converge on similar putative pathological mechanisms. This review aims to summarize the findings and questions emerging from the field’s quest to decipher how C9ORF72 repeat expansions cause the devastating diseases collectively referred to as "c9ALS/FTD."
Source: Cold Spring Harbor perspectives in medicine - Category: Research Authors: Tags: Prion Diseases PERSPECTIVES Source Type: research

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Abstract A microsatellite expansion mutation in C9orf72 is the most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). The expansion mutation leads to C9orf72 loss of function, RNA foci formation, and generation of five species of non-AUG RAN translated dipeptide repeat proteins (DPRs), such as poly(GA), poly(GP), poly(GR), poly(PA), and poly(PR). Although one cell can contain more than type of DPRs, information about interplay between different DPR species is limited. Here we show that the combined expression of distinct C9orf72-derived dipeptide repeat species produces...
Source: International Journal of Biological Macromolecules - Category: Biochemistry Authors: Tags: Int J Biol Macromol Source Type: research
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Source: Molecular Neurobiology - Category: Neurology Source Type: research
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Source: Neuroscience Bulletin - Category: Neuroscience Source Type: research
AbstractA GGGGCC hexanucleotide repeat expansion within theC9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Sense and antisense repeat-containing transcripts undergo repeat-associated non-AUG-initiated translation to produce five dipeptide proteins (DPRs). The polyGR and polyPR  DPRs are extremely toxic when expressed in Drosophila neurons. To determine the mechanism that mediates this toxicity, we purified DPRs from the Drosophila brain and used mass spectrometry to identify the in vivo neuronal DPR interactome. PolyGR and p...
Source: Acta Neuropathologica - Category: Neurology Source Type: research
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Source: Parkinsons Disease - Category: Neurology Tags: Parkinsons Dis Source Type: research
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Source: Praxis - Category: General Medicine Authors: Tags: Praxis (Bern 1994) Source Type: research
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Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research
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Source: Swiss Medical Weekly - Category: General Medicine Authors: Tags: Swiss Med Wkly Source Type: research
ConclusionsThe present work is the first in vivo FDG-PET study showing the heterogeneous patterns of brain regional hypo- and hypermetabolism in single patients sharing C9orf72 mutation. Brain hypometabolism was consistent with the clinical phenotypes, supporting the diagnostic importance of neuroimaging functional biomarkers to capture at single-subject level specific brain dysfunction.
Source: Neurological Sciences - Category: Neurology Source Type: research
Mary Kay Floeter, Tania F. Gendron
Source: Frontiers in Neurology - Category: Neurology Source Type: research
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