Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss.
Acta Neuropathol
; 134(2): 241-254, 2017 08.
Article
em En
| MEDLINE
| ID: mdl-28409281
Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Medula Espinal
/
Corpos de Inclusão
/
Doenças do Sistema Nervoso Central
/
Expansão das Repetições de DNA
/
Proteína C9orf72
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Acta Neuropathol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Alemanha