NGN2-induced neurons as a model of C9orf72 hexanucleotide repeat expansion-associated frontotemporal dementia
Year: 2023
Type: dissertation
Abstract: Frontotemporal dementia (FTD) is a group of neurodegenerative disorders and a common cause of early-onset dementia, where a hexanucleotide expansion in the C9orf72 gene is the most frequent genetic cause for the disease.C9orf72 causes neuronal damage through three main disease mechanisms, which are C9orf72 haploinsufficiency and formation of RNA foci and dipeptide repeat proteins (DPRs), but the exact molecular pathways need further elucidation.Deficiencies in neurotransmitter systems are common in FTD patients, including changes in glutamatergic and GABAergic systems.Using patient-derived induced pluripotent stem cells (iPSCs) is an increasingly common disease model, and differentiation from iPSCs can be guided to produce different cell types specifically.The aim of this study was to set up a protocol utilizing exogenous NGN2 expression to differentiate glutamatergic neurons from patient-derived iPSCs and to compare cells from patients carrying the C9orf72 hexanucleotide repeat expansion (C9+), sporadic FTD patients (C9-) and healthy controls.Furthermore, this model was optimized for more advanced C9orf72-related FTD research.NGN2-driven differentiation successfully produced glutamatergic neurons, and the neurons expressed synaptic proteins, showing potential for synapse formation and activity.These results are in line with other reports of NGN2 differentiation.C9+ neurons displayed RNA foci, but studying DPR expression requires more specific antibodies.There were no significant differences in the expression of other proteins commonly altered in FTD, such as TDP-43 and p62.Further experiments are needed to gain information about the maturity and synaptic functionality of these neurons and to describe the disease-associated phenotypes with more accuracy.
Author: Pekkala, Viivi
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7215644601