GRN-/- iPSC-derived cortical neurons recapitulate the pathological findings of both frontotemporal lobar degeneration and neuronal ceroidolipofuscinosis.
Neurobiol Dis
; 175: 105891, 2022 12.
Article
em En
| MEDLINE
| ID: mdl-36220610
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Pluripotentes Induzidas
/
Degeneração Lobar Frontotemporal
/
Demência Frontotemporal
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Revista:
Neurobiol Dis
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Itália