Aperçu du projet
A G4C2 repeat expansion in C9orf72 (chromosome 9 open reading frame 72), a gene of unclear function, is the most frequent genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (C9-ALS/FTD). The repeat expansions cause transcriptional downregulation of the C9orf72 mRNA resulting in loss of C9orf72 protein. As such it is essential to elucidate the function of C9orf72 to understand its role in the pathogenesis of ALS/FTD. We have demonstrated that C9orf72 is enriched in post synaptic densities (PSDs) of mouse forebrain. Loss of C9orf72 causes an upregulation of the GluA1 AMPA receptor in PSDs of C9orf72 knockout mice (C9-KO), and this is associated with decreased levels of Rab39b. Using snRNA-seq to uncover the cell type specific changes in frontal cortex of C9orf72-ALS/FTD cases, we identified Gene Ontology Terms for the most differentially expressed genes in excitatory neurons as ‘glutamate receptor trafficking’, ‘regulation of post synapse organization’ and ‘regulation of neuronal synaptic plasticity’. Recent reports have also demonstrated elevated levels of GluA1 in iPSC-derived motor neurons (iMNs) from C9-ALS/FTD patients, causing increased vulnerability to glutamate, with these phenotypes rescued by ectopic expression of C9orf72. Similar effects are observed in C9-KO iMNs, demonstrating a direct role for C9orf72 in regulating GluA1 levels, with C9orf72 deficiency predisposing to glutamate hyperexcitability. Here we propose to establish the relevance of these findings in vivo through investigating the effects of C9orf72 deficiency on inducing neuronal hyperexcitability in C9-KO mice.