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GRN−/− iPSC-derived cortical neurons recapitulate the pathological findings of both frontotemporal lobar degeneration and neuronal ceroidolipofuscinosis
GRN−/− iPSC-derived cortical neurons recapitulate the pathological findings of both frontotemporal lobar degeneration and neuronal ceroidolipofuscinosis
- Source :
- Neurobiology of Disease, Vol 175, Iss , Pp 105891- (2022)
- Publication Year :
- 2022
- Publisher :
- Elsevier, 2022.
-
Abstract
- Heterozygous mutations in the gene coding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) while homozygous mutations are linked to neuronal ceroidolipofuscinosis (NCL). While both FTLD/NCL pathological hallmarks were mostly investigated in heterozygous GRN+/− brain tissue or induced pluripotent stem cell (iPSC)-derived neurons, data from homozygous GRN−/− condition are scarce, being limited to a postmortem brain tissue from a single case. Indeed, homozygous GRN−/− is an extremely rare condition reported in very few cases. Our aim was to investigate pathological phenotypes associated with FTLD and NCL in iPSC-derived cortical neurons from a GRN−/− patient affected by NCL. iPSCs were generated from peripheral blood of a GRN wt healthy donor and a GRN−/− patient and subsequently differentiated into cortical neurons. Several pathological changes were investigated, by means of immunocytochemical, biochemical and ultrastructural analyses. GRN−/− patient-derived cortical neurons displayed both TDP-43 and phospho-TDP-43 mislocalization, enlarged autofluorescent lysosomes and electron-dense vesicles containing storage material with granular, curvilinear and fingerprints profiles. In addition, different patterns in the expression of TDP-43, caspase 3 and cleaved caspase 3 were observed by biochemical analysis at different time points of cortical differentiation. At variance with previous findings, the present data highlight the existence of both FTLD- and NCL-linked pathological features in GRN−/− iPSC-derived cortical neurons from a NCL patient. They also suggest an evolution in the appearance of these features: firstly, FTLD-related TDP-43 alterations and initial NCL storage materials were detected; afterwards, mainly well-shaped NCL storage materials were present, while some FTLD features were not observed anymore.
Details
- Language :
- English
- ISSN :
- 1095953X and 16896793
- Volume :
- 175
- Issue :
- 105891-
- Database :
- Directory of Open Access Journals
- Journal :
- Neurobiology of Disease
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.840ac6da1584dd5b39f1a168967932f
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.nbd.2022.105891