Frontotemporal Dementia (FTD) is a neurodegenerative disorder characterized by clinical and neuropathological heterogeneity and high genetic complexity. Granulin gene (GRN) is an important predisposing factor for FTD and the proposed disease mechanism is deficiency of the protein. Progranulin (PGRN) is a secreted glycoprotein with several roles and expressed across a wide range of tissues including the brain, however, the neurobiology of this protein remains unclear. It is known that FTD patients with PGRN deficiency show ubiquitin-positive inclusions in the brain with accumulation of TDP-43 and do not show tau protein aggregates, altered protein conformations or aggregates trigger neuronal dysfunction and can spread to neighboring neurons. We previously studied three pedigrees of Southern Italian extraction in whom FTD segregates with autosomal dominant inheritance patterns. We identified in all the available patients in these three familial cases a rare GRN gene exon six deletion g10325_10331delCTGCTGT (relative to nt 1 in NG_007886.1), alias Cys157LysfsX97. We identified and analyzed the effect of the GRN mutation at transcriptional and translational levels revealing that this deletion lead to haploinsufficiency of the protein. Our findings provide further support for a previously proposed role for the GRN gene in the genetic etiology of FTD and its phenotypic variability. I am now presenting a neuronal cellular model generated by CRISPR-Cas9 for the study of mechanisms potentially involved in neuronal cell death following PGRN deficiency. I am testing the behave of TDP-43 aggregates and their spreading in this cellular model thus to analyze whether there are molecular changes in tight association with this mutation. It is my hypothesis that specific FTD pathological targets exist and my task is to first identify molecular defects and second develop strategies for the rescue of dysfunctional neurodegenerative phenotypes.
CRISPR-Cas9 neuronal cell model: identification of neurodegenerative mechanisms in Frontotemporal Dementia (FTD).
2017
Abstract
Frontotemporal Dementia (FTD) is a neurodegenerative disorder characterized by clinical and neuropathological heterogeneity and high genetic complexity. Granulin gene (GRN) is an important predisposing factor for FTD and the proposed disease mechanism is deficiency of the protein. Progranulin (PGRN) is a secreted glycoprotein with several roles and expressed across a wide range of tissues including the brain, however, the neurobiology of this protein remains unclear. It is known that FTD patients with PGRN deficiency show ubiquitin-positive inclusions in the brain with accumulation of TDP-43 and do not show tau protein aggregates, altered protein conformations or aggregates trigger neuronal dysfunction and can spread to neighboring neurons. We previously studied three pedigrees of Southern Italian extraction in whom FTD segregates with autosomal dominant inheritance patterns. We identified in all the available patients in these three familial cases a rare GRN gene exon six deletion g10325_10331delCTGCTGT (relative to nt 1 in NG_007886.1), alias Cys157LysfsX97. We identified and analyzed the effect of the GRN mutation at transcriptional and translational levels revealing that this deletion lead to haploinsufficiency of the protein. Our findings provide further support for a previously proposed role for the GRN gene in the genetic etiology of FTD and its phenotypic variability. I am now presenting a neuronal cellular model generated by CRISPR-Cas9 for the study of mechanisms potentially involved in neuronal cell death following PGRN deficiency. I am testing the behave of TDP-43 aggregates and their spreading in this cellular model thus to analyze whether there are molecular changes in tight association with this mutation. It is my hypothesis that specific FTD pathological targets exist and my task is to first identify molecular defects and second develop strategies for the rescue of dysfunctional neurodegenerative phenotypes.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
