Ruxandra Mutihac Dafinca
Postdoctoral Research Fellow
My research focuses on modelling amyotrophic lateral sclerosis in neurons obtained by differentiating induced pluripotent stem cells (iPSCs) derived from patient fibroblasts.
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal adult-onset motor neuron disorder characterized by the degeneration of motor neurons in the brain and spinal cord, leading to death within 3-5 years. The recently discovered hexanucleotide intronic GGGGCC expansion in chromosome 9 open reading frame 72 (C9orf72) establishes a firm genetic link between ALS and FTLD, being classified as the most common cause of familial and sporadic ALS and FTLD,
One major drawback in the studies of motor neurons disease has been the lack of relevant cell culture models and our inability to directly study human motor neurons from patients who carry the specific genetic background conferring disease susceptibility. However, we are now able to use stem cell technology to generate induced pluripotent stem cells (iPSCs) from the fibroblasts of C9orf72 patients and differentiate them to motor neurons for functional investigations. Induced pluripotent stem cells provide tremendous opportunities because they can be derived from accessible tissues such as peripheral blood and skin fibroblasts and then, by directed differentiation in vitro, they can be used to generate neuronal cells. The neurons obtained by iPSCs derivation have the advantage of carrying disease-specific genetic profiles and display characteristic neurodegenerative traits.
I am currently investigating the phenotypes of motor neurons derived from iPSCs of ALS patients that carry C9orf72 mutations by looking at differences in calcium homeostasis, excitotoxicity and autophagy impairments.
Motor neurons derived from the iPSCs of patients fibroblasts that carry mutations and reproduce ALS phenotypes will provide the ultimate in vitro model for drug screening in collaboration with pharmaceutical companies.
C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia.
Aoki Y. et al, (2017), Brain, 140, 887 - 897
C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell-Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.
Dafinca R. et al, (2016), Stem Cells, 34, 2063 - 2078
Development of LNA gapmer oligonucleotide based therapy for FTD/ALS caused by the C9orf72 repeat expansion
Aoki Y. et al, (2015), NEUROMUSCULAR DISORDERS, 25, S315 - S316
TARDBP pathogenic mutations increase cytoplasmic translocation of TDP-43 and cause reduction of endoplasmic reticulum Ca²⁺ signaling in motor neurons.
Mutihac R. et al, (2015), Neurobiol Dis, 75, 64 - 77
LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.
Alegre-Abarrategui J. et al, (2009), Hum Mol Genet, 18, 4022 - 4034