Selectivity is the rule, rather than the exception, in neurodegenerative disease. A retired telephone operator carrying a C9orf72 expansion developed phonagnosia, a selective impairment of voice recognition, contrasting with intact person knowledge and recognition of faces, as a presenting sign of genetically confirmed fronto-temporal dementia. Since the dysfunction in this patient fell into his area of professional expertise, we discuss if overload in voice related neural networks might have caused failure propagating to connected nodes. The interaction with downstream molecular events, triggered by the C9orf72 expansion, may have led to breakdown at the network level, leading to this specific phenotype.
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| http://dx.doi.org/10.1016/j.cortex.2020.05.022 | DOI Listing |
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Alzheimers Dement
December 2024
Dementia Research Centre, Queen Square Institute of Neurology, University College London, London, UK.
Background: GRN mutations are a common cause of frontotemporal dementia (FTD), with previous studies linking granulin deficiency to reduced bis(monoacylglycerol)phosphate (BMP) levels, which ultimately impairs ganglioside degradation. BMP is involved in the lysosomal functions within cells, as it facilitates the adhesion of hydrolases and activator proteins where the lysosomal membranes meet, therefore a lack of BMP could impact lysosome function and integrity. We hypothesised that urine levels of BMP isoforms will be lower in FTD patients with GRN haploinsufficiency, as a reflection of reduced BMP in neural tissues, when compared to those with FTD caused by C9orf72 expansions and MAPT mutations, or healthy controls.
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Alzheimers Dement
December 2024
UCSF Weill Institute for Neurosciences, San Francisco, CA, USA.
Background: Efforts to genetically reverse C9orf72 pathology have been hampered by our incomplete understanding of the regulation of this complex locus.
Method: We generated five different genomic excisions at the C9orf72 locus in a patient-derived iPSC line and a WT line (11 total isogenic lines), and examined gene expression and pathological hallmarks of C9 FTD/ALS in motor neurons differentiated from these lines. Comparing the excisions in these isogenic series removed the confounding effects of different genomic backgrounds and allowed us to probe the effects of specific genomic changes.
The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is an intronic GC repeat expansion in C9orf72. The repeats undergo bidirectional transcription to produce sense and antisense repeat RNA species, which are translated into dipeptide repeat proteins (DPRs). As toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs, targeting both strands may provide the most effective therapeutic strategy.
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Nat Commun
January 2025
Department of Bioengineering, The Grainger College of Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA.
An abnormal expansion of a GGGGCC (GC) hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we develop here a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the GC repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci, reduced the production of a dipeptide repeat protein, and reversed transcriptional deficits.
View Article and Find Full Text PDFUnlabelled: The neurodegenerative disorder Frontotemporal Dementia (FTD) can be caused by a repeat expansion (GGGGCC; G4C2) in C9orf72. The function of wild-type C9orf72 and the mechanism by which the C9orf72-G4C2 mutation causes FTD, however, remain unresolved. Diverse disease models including human brain samples and differentiated neurons from patient-derived induced pluripotent stem cells (iPSCs) identified some hallmarks associated with FTD, but these models have limitations, including biopsies capturing only a static snapshot of dynamic processes and differentiated neurons being labor-intensive, costly, and post-mitotic.
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