Synaptic deficits in C9orf72-ALS/FTD patient-derived human stem cell differentiated neurons and in vivo models of C9orf72
Lorenzini I1, Ghaffari L1, Lall D2, Levy J1, Burciu C1, Shenoy D1, Twishime N1, Bhatia D1, Baloh R2, Sattler R1
1Neurobiology Division, Barrow Neurological Institute, Phoenix, AZ, USA
2Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
The hexanucleotide repeat expansion GGGGCC (G4C2) found in the non-coding region of the C9orf72 (C9) gene represents the most common genetic abnormality in amyotrophic lateral sclerosis (ALS) (40-50%) and frontotemporal dementia (FTD) (10-30%). ALS and FTD patients have genetic, pathologic and symptomatic overlap. Therefore, understanding the molecular mechanisms of disease pathogenesis in this ALS/FTD disease spectrum could lead to the development of novel therapeutic strategies. Cognitive decline as seen in normal ageing or Alzheimer's disease (AD) is characterized by changes in neuronal morphology, spine density and progressive synapse loss. We hypothesize that similar mechanisms are responsible for the dementia symptoms caused by the C9 mutation and that these events arise early during disease progression before any neurodegeneration has occurred. Furthermore, based on recent findings in AD and FTD, we hypothesize that this synaptic dysfunction may involve theneural-immune complement pathway. Here we present preliminary data supporting this hypothesis using C9-ALS/FTD patient-derived human induced pluripotent stem cells differentiated into motor neurons (hiPSC-MNs) and cortical neurons (hiPSC-CNs), in addition to C9 mouse models. We found significant changes in dendritic branching, dendritic length, spine density and detected alterations in the expression pattern of synaptic proteins in hiPSC neurons. We also observed changes in neuronal excitability using longitudinal micro-electrode array analysis. Similar changes in dendritic arborization and dendritic length were observed in homozygous C9orf72 -/- knockout mice. In addition, increased complement pathway activation and decreased gene expression of pre-synaptic markers were observed in this C9 mouse model. Our data suggest that synaptic deficits are present in C9 ALS/FTD which are likely to be triggered by aberrant neural-immune interactions. These synaptic dysfunctions are hypothesized to contribute to cognitive impairment and neuronal cell death found in C9orf72 patients.