Table 1 TDP-43 pathology in human models of PGRN deficiency
From: Progranulin deficiency in the brain: the interplay between neuronal and non-neuronal cells
Model | TDP-43 pathology | References |
|---|---|---|
Patient-derived models | ||
CLN11 patient iPSC -derived cortical neurons with homozygous PGRN p.T272SfsX pathogenic variant | Increases of cytoplasmic TDP-43 and p-TDP-43, as well as cleaved TDP-43 C-terminal fragments | [118] |
bvFTD patient iPSC-derived neurons with heterozygous PGRN p.S116X pathogenic variant | Higher redistribution of TDP-43 from the nucleus to the cytoplasm | [9] |
FTD patient iPSC-derived cortical neurons with heterozygous GRN IVS1 + 5G > C splicing mutation | TDP-43 displays normal nuclear staining with no aggregates | [136] |
FTD patient iPSC-derived cortical neurons with heterozygous PGRN p.R493X pathogenic variant | TDP-43 aggregates in the cytoplasm; mutant TDP-43 shows a doubled half-life | [56] |
iPSC-derived cortical neurons from three FTD patients with heterozygous PGRN p.A9D pathogenic variant | Reduced nuclear TDP-43 and increased insoluble TDP-43 | [45] |
Lymphoblastoid cell lines (LCLs) from patients carrying a heterozygous PGRN p.T272SfsX10, p.C149LfsX10, p.Q341X, or IVS1-2A > G; or homozygous p.T272SfsX10 PGRN pathogenic variant | Increased p-TDP-43 levels in LCLs and EVs; 25-kDa fragments of TDP-43 are only present in patient LCLs | [119] |
Monocyte-derived induced microglia (iMGs) from FTD patients with PGRN p.M1? and p.W147X pathogenic variant | Cytoplasmic aggregation of phosphorylated and ubiquitinated TDP-43; lipid droplet accumulation, lysosomal abnormalities, and impaired phagocytosis | [14] |
FTD patient-derived fibroblasts with PGRN mutations p.M1? and p.W147X pathogenic variant | Cytoplasmic increases of p-TDP-43 | [14] |
GRN silencing-based models | ||
SH-SY5Y, HeLa and HEK293T cell lines with downregulation or upregulation of GRN by siRNA/overexpression, respectively | Cell line-specific accumulation of sarkosyl-insoluble TDP-43 in PGRN-deficient cells | [40] |
Human neural progenitor cells from aborted female fetus; stable GRN silencing by shRNA | Increases of poly-ubiquitinated proteins | [113] |
SH-SY5Y cells with stable GRN silencing by shRNA | TDP-43-positive intranuclear inclusions | [206] |
Human primary skin fibroblasts from neurologically healthy donors, with transient GRN silencing by siRNA | Increased production of a 25 kDa TDP-43 C-terminal cleavage product | [205] |
2D coculture model of neurons and astrocytes, with GRN knockout either in neurons or in astrocytes | Lack of overt TDP-43 pathology at 4th week of coculture; STMN2 mis-splicing at 4th week of coculture, which can be rescued by recombinant PGRN | [11] |
3D brain organoids composed of GRN−/− or GRN+/+ neurons and astrocytes | TDP-43 mislocalization in both GRN−/− astrocytes and GRN+/+ neurons, or GRN+/+ astrocytes and GRN−/− neurons; cytoplasmic p-TDP-43 inclusions at 4th week of coculture; STMN2 mis-splicing only in organoids containing PGRN-deficient astrocytes, independently of neuronal PGRN status | [11] |
Cortical organoids transplanted with GRN−/− induced astrocytes (iASTs) | Extranuclear accumulation of TDP-43 in neurons | [7] |