期刊
ACTA NEUROPATHOLOGICA
卷 134, 期 2, 页码 241-254出版社
SPRINGER
DOI: 10.1007/s00401-017-1711-0
关键词
ALS; FTLD; FTD; MND; C9orf72; Neurodegeneration; Neurological disorder; Mouse model
资金
- NOMIS foundation
- Hans und Ilse Breuer Foundation
- Munich Cluster of Systems Neurology (SyNergy)
- European Community [617198]
- National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke [P01NS084974, R01 NS093865-01]
- ALS Association
- Muscular Dystrophy Association
- German Federal Ministry of Education and Research [01KX1012]
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.
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