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Nat Commun ; 9(1): 347, 2018 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-29367641

RESUMO

Mutations in C9ORF72 are the most common cause of familial amyotrophic lateral sclerosis (ALS). Here, through a combination of RNA-Seq and electrophysiological studies on induced pluripotent stem cell (iPSC)-derived motor neurons (MNs), we show that increased expression of GluA1 AMPA receptor (AMPAR) subunit occurs in MNs with C9ORF72 mutations that leads to increased Ca2+-permeable AMPAR expression and results in enhanced selective MN vulnerability to excitotoxicity. These deficits are not found in iPSC-derived cortical neurons and are abolished by CRISPR/Cas9-mediated correction of the C9ORF72 repeat expansion in MNs. We also demonstrate that MN-specific dysregulation of AMPAR expression is also present in C9ORF72 patient post-mortem material. We therefore present multiple lines of evidence for the specific upregulation of GluA1 subunits in human mutant C9ORF72 MNs that could lead to a potential pathogenic excitotoxic mechanism in ALS.


Assuntos
Proteína C9orf72/genética , Neurônios Motores/patologia , Receptores de AMPA/metabolismo , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/metabolismo , Sistemas CRISPR-Cas , Cálcio/metabolismo , Expansão das Repetições de DNA , Marcação de Genes , Humanos , Receptores de AMPA/genética , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
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