Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss

Acta Neuropathol. 2017 Aug;134(2):241-254. doi: 10.1007/s00401-017-1711-0. Epub 2017 Apr 13.


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.

Keywords: ALS; C9orf72; FTD; FTLD; MND; Mouse model; Neurodegeneration; Neurological disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Stem / metabolism
  • Brain Stem / pathology
  • C9orf72 Protein / genetics*
  • C9orf72 Protein / metabolism
  • Calcium-Binding Proteins / metabolism
  • Central Nervous System Diseases / physiopathology*
  • Cytokines / metabolism
  • DNA Repeat Expansion / genetics*
  • Embryo, Mammalian
  • Gene Expression Regulation / genetics
  • Hippocampus / cytology
  • Humans
  • Inclusion Bodies / genetics
  • Inclusion Bodies / pathology*
  • Inflammation / genetics
  • Inflammation / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / pathology
  • Nuclear Proteins / metabolism
  • Psychomotor Performance
  • Spinal Cord / pathology*


  • C9orf72 Protein
  • Calcium-Binding Proteins
  • Cytokines
  • Nuclear Proteins