Deregulated expression of a longevity gene, Klotho , in the C9orf72 deletion mice with impaired synaptic plasticity and
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LETTER TO THE EDITOR
Deregulated expression of a longevity gene, Klotho, in the C9orf72 deletion mice with impaired synaptic plasticity and adult hippocampal neurogenesis Wan Yun Ho1, Sheeja Navakkode1,2, Fujia Liu1, Tuck Wah Soong1,3 and Shuo‑Chien Ling1,3,4,5*
Abstract 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 expan‑ sions 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 longterm 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 gran‑ ule 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. Keywords: Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), C9ORF72, Klotho, Longevity, Dentate gyrus, adult neurogenesis, Long-term potentiation (LTP), Long-term depression (LTD) Hexanucleotide repeat expansion of C9ORF72 is the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [10, 33]. Although loss of C9orf72 does not cause neurodegeneration per se [5, 18, 21, 31], reduced C9orf72 expression exacerbates the gain of toxicities inflicted by the repeat expansion [36, 37, 43]. Specifically, loss of C9orf72 triggers systemic and neuronal inflammation [5, 18, 31], in part, through altering gut microbiota [6]. Molecularly, *Correspondence: [email protected]; [email protected] 5 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Tahir Foundation Building, MD1, 16‑03‑H, 12 Science Drive 2, Singapore 117549, Singapore Full list of author information is available at the end of the article
C9ORF72 acts as GDP/GTP exchange factors (GEFs) for several small RAB GTPases that are potentially involved in membrane trafficking [1, 35, 40, 41]. Furthermore, we and others have showed that C9ORF72 associates with ULK1-autophagy initiation complex to regulate autophagy [17, 19, 35, 38–41] and C9ORF72 is required for neuronal and dendritic morphogenesis via ULK1-mediated autophagy [17]. In addition, increased C9ORF72 expression due to intermediate repeat expansion disrupts autophagy a
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