Senior Postdoctoral Research Fellow
Modelling Amyotrophic Lateral Sclerosis in induced pluripotent stem cell-derived motor neurons from patients carrying C9orf72 and TDP-43 mutations
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,
In our lab, we use 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 TDP-43 and C9orf72 mutations by looking at differences in nucleocytoplasmic transport and mitochondrial deficits. I am also using CRISPR/Cas9 genome engineering to correct the mutations in these patient lines.
As an Oxford-BMS fellow, my aim is to identify novel targets within these pathways that can be used in drug screening.
Impairment of mitochondrial calcium buffering links mutations in C9orf72 and TARDBP in iPS-derived motor neurons from patients with ALS/FTD
DAFINCA R. et al, (2020), Stem Cell Reports
Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction.
Gordon D. et al, (2019), Neurobiol Dis, 121, 148 - 162
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
Absence of wide-spread mis-splicing in the preclinical phase of a native promoter driven TDP-43 mouse model of ALS
Scaber J. et al, (2016), EUROPEAN JOURNAL OF NEUROLOGY, 23, 797 - 797