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  • Active Research Projects: Sattler Lab

    Over the last few years, extensive research from our laboratory and others on the role of the (G4C2)n repeat expansion in C9orf72 has led to the proposal of different disease-causing mechanism for mutant C9:

    1. protein loss-of-function,
    2. toxic RNA gain-of-function
    3. toxicity caused by repeat-associated non-ATG initiated (RAN) translation, which leads to the formation of dipeptide repeat proteins (DRPs)

    In addition, a recent hypothesis from our laboratory as well as others suggests that mutant C9orf72 leads to deficits in nuclear-cytoplasmic trafficking of RNAs and/or proteins due to either one of the mechanisms described above or, most likely, a combination of all three. Our laboratory is currently studying different downstream pathways that we hypothesize are altered due to the pathogenic phenotypes described above.

    Synaptopathy in C9orf72

    We hypothesize that progressive synaptic loss and dysfunction, often described as synaptopathy, is an early event during disease development that has long-lasting effects on cognitive function.


    Fluorescent images of hiPSC-neurons overexpressing eGFP protein (green) and labeled for MAP2 (red) and DAPI (blue).

    In support of this, we have preliminary evidence of synaptic loss and dendritic remodeling in human cortical neurons differentiated from C9 amyotrophic lateral sclerosis (ALS) patient-derived human induced pluripotent stem cells (hiPSCs). We are investigating whether these brain-region specific synaptic dysfunctions found in C9 ALS are equally present in neurons from non-C9 ALS patients, C9 frontotemporal dementia (FTD) patients, and non-C9 FTD patients. We are also investigating whether or not they are triggered by similar molecular mechanisms and at similar points in time as these diseases progress. Confocal microscopy of hiPSC-neurons as well as novel C9orf72 mouse models will be used to study morphological and functional synaptic deficits.

    A basic understanding of synaptic dysfunction in ALS and FTD will lead to the identification of specific therapeutic targets aimed at stratified patient populations to enable better and more successful clinical trials.

    Role of RNA editing in C9orf72


    Fluorescent images of hiPSC-neurons labeled for editing enzyme ADAR2 (red), motor neuron marker Chat (green) and nuclear marker DAPI (blue). The comparison between healthy control hiPSC-neurons and those derived from C9 ALS patients shows a clear distinction in the ADAR2 expression pattern shifting from nuclear (Ctrl) to cytoplasmic (C9).

    We hypothesize that one molecular mechanism that leads to synaptopathy and hyperexcitability in C9orf72 neurons is aberrant RNA editing of varying synaptic proteins. We have preliminary evidence that a major editing enzyme, ADAR2, is mislocalized in C9orf72 due to the nuclear cytoplasmic trafficking deficits. As a result, we show decreased RNA editing efficiency of ADAR2 targets, including the glutamate receptor subunit GluA2.

    Editing of GluA2 determines the Ca2+ permeability of the AMPA receptor, which plays a significant role in synaptic plasticity as well as vulnerability to excitotoxicity.  We use live imaging techniques to study cell survival and Ca dynamics in C9orf72 hiPSC neurons. In addition, RNA seq analyses are performed to study editing deficiencies of other ADAR2 targets.

    Pilot Projects

    In addition to these major research projects, we have several small pilot projects in collaboration with local investigators from the valley:

    1. Studies on genetic forms of cerebral palsy using patient-derived hiPSC neurons in collaboration with Dr. Michael Kruer (Phoenix Children Hospital, University of Arizona)
    2. Investigation of the role of metabolic pathways in TDP-43 ALS with Dr. Daniela Zarnescu (University of Arizona)
    3. Investigation of the role of an ALS patient-specific mutation in a copper transporter protein (ATP7A) using patient fibroblasts and hiPSC neurons with Dr. Robert Bowser (BNI)

    About Barrow Neurological Institute
    Since our doors opened as a regional specialty center in 1962, we have grown into one of the premier destinations in the world for neurology and neurosurgery. Our experienced, highly skilled, and comprehensive team of neurological specialists can provide you with a complete spectrum of care–from diagnosis through outpatient neurorehabilitation–under one roof. Barrow Neurological Institute: Discover. Educate. Heal.