The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration.
Nat Neurosci
; 18(7): 988-96, 2015 Jul.
Article
in En
| MEDLINE
| ID: mdl-26005849
ABSTRACT
Genetic epilepsy and neurodegenerative diseases are two common neurological disorders that are conventionally viewed as being unrelated. A subset of patients with severe genetic epilepsies who have impaired development and often go on to die of their disease respond poorly to anticonvulsant drug therapy, suggesting a need for new therapeutic targets. Previously, we reported that multiple GABAA receptor epilepsy mutations result in protein misfolding and abnormal receptor trafficking. We have now developed a model of a severe human genetic epileptic encephalopathy, the Gabrg2(+/Q390X) knock-in mouse. We found that, in addition to impairing inhibitory neurotransmission, mutant GABAA receptor γ2(Q390X) subunits accumulated and aggregated intracellularly, activated caspase 3 and caused widespread, age-dependent neurodegeneration. These findings suggest that the fundamental protein metabolism and cellular consequences of the epilepsy-associated mutant γ2(Q390X) ion channel subunit are not fundamentally different from those associated with neurodegeneration. Our results have far-reaching relevance for the identification of conserved pathological cascades and mechanism-based therapies that are shared between genetic epilepsies and neurodegenerative diseases.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, GABA-A
/
Neurodegenerative Diseases
/
Epilepsy
Type of study:
Etiology_studies
/
Prognostic_studies
Limits:
Adult
/
Animals
/
Female
/
Humans
Language:
En
Journal:
Nat Neurosci
Journal subject:
NEUROLOGIA
Year:
2015
Document type:
Article
Affiliation country:
United States