Deregulated expression of a longevity gene, Klotho, in the C9orf72 deletion mice with impaired synaptic plasticity and adult hippocampal neurogenesis

Autor: Tuck Wah Soong, Sheeja Navakkode, Fujia Liu, Shuo-Chien Ling, Wan Yun Ho
Přispěvatelé: Lee Kong Chian School of Medicine (LKCMedicine)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Neurogenesis
Longevity
C9ORF72
Hippocampal formation
Biology
Frontotemporal dementia (FTD)
Hippocampus
Klotho
lcsh:RC346-429
Pathology and Forensic Medicine
Mice
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
medicine
Animals
Medicine [Science]
Amyotrophic lateral sclerosis (ALS)
Letter to the Editor
Klotho Proteins
lcsh:Neurology. Diseases of the nervous system
Glucuronidase
Mice
Knockout
Long-term potentiation (LTP)
Neuronal Plasticity
C9orf72 Protein
Dentate gyrus
Amyotrophic Lateral Sclerosis
Dentate gyrus
adult neurogenesis
Neurodegenerative Diseases
Long-term potentiation
Long-term depression (LTD)
Granule cell
030104 developmental biology
medicine.anatomical_structure
nervous system
Schaffer collateral
Frontotemporal Dementia
Synaptic plasticity
Neurology (clinical)
Transcriptome
Neuroscience
030217 neurology & neurosurgery
Zdroj: Acta Neuropathologica Communications, Vol 8, Iss 1, Pp 1-7 (2020)
Acta Neuropathologica Communications
ISSN: 2051-5960
Popis: Hexanucleotide repeat expansion of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Synergies between loss of C9ORF72 functions and gain of toxicities from the repeat expansions contribute to C9ORF72-mediated pathogenesis. However, how loss of C9orf72 impacts neuronal and synaptic functions remains undetermined. Here, we showed that long-term potentiation at the dentate granule cells and long-term depression at the Schaffer collateral/commissural synapses at the area CA1 were reduced in the hippocampus of C9orf72 knockout mice. Using unbiased transcriptomic analysis, we identified that Klotho, a longevity gene, was selectively dysregulated in an age-dependent manner. Specifically, Klotho protein expression in the hippocampus of C9orf72 knockout mice was incorrectly enriched in the dendritic regions of CA1 with concomitant reduction in granule cell layer of dentate gyrus at 3-month of age followed by an accelerating decline during aging. Furthermore, adult hippocampal neurogenesis was reduced in C9orf72 knockout mice. Taken together, our data suggest that C9ORF72 is required for synaptic plasticity and adult neurogenesis in the hippocampus and Klotho deregulations may be part of C9ORF72-mediated toxicity. Ministry of Education (MOE) National Medical Research Council (NMRC) Published version This work was supported by grants to S.‑C. Ling from the Swee Liew‑Wadsworth Endowment fund, National University of Singapore (NUS), National Medical Research Council (NMRC/OFIRG/0001/2016 and NMRC/OFIRG/0042/2017) and Ministry of Education (MOE2016‑T2‑1‑024), Singapore.
Databáze: OpenAIRE
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