Similar lysosomal abnormalities in cortex of patients with sporadic FTLD‐TDP type A and patients with FTD‐GRN

Background Loss‐of‐function mutations in progranulin (GRN) are an autosomal dominant cause of frontotemporal dementia (FTD). Progranulin is critical for maintenance of lysosomal function. Patients with FTD due to GRN mutations (FTD‐GRN) exhibit signs of lysosomal dysfunction, which may contribute to FTD‐GRN pathogenesis. To assess the potential involvement of lysosomal dysfunction in FTD of sporadic origin, we investigated whether the lysosomal abnormalities of FTD‐GRN are also present in patients with sporadic frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐TDP) type A, the same FTLD subtype found in patients with FTD‐GRN. Method We used enzyme activity assays, western blot, immunostaining, and Nanostring analysis to assess changes in lysosomal protein and gene expression in orbital and occipital cortex of patients with FTD‐GRN, sporadic FTLD‐TDP type A, or controls. We measured lipofuscin using autofluorescence and staining with Sudan Black B. In follow‐up studies, we assessed these lysosomal markers in a transgenic mouse line expressing wild‐type human TDP‐43 under the Thy1 promoter. Result We found similar lysosomal abnormalities in orbital cortex of patients with FTD‐GRN or sporadic FTLD‐TDP type A. Both FTD patient groups exhibited elevated levels of lysosomal enzymes and membrane proteins, higher expression of many lysosomal genes, and greater lipofuscin accumulation than controls. These changes were largely absent in occipital cortex from both groups. Analysis of frontal cortex from a transgenic mouse model of TDP‐opathy also revealed elevated levels of some lysosomal proteins and elevated lipofuscin levels. Conclusion These studies indicate that the lysosomal abnormalities of patients with FTD‐GRN may be more closely associated with TDP‐opathy or neurodegeneration than with progranulin insufficiency. Orbital cortex, an affected brain region in FTD‐GRN, exhibited elevated lysosomal protein levels and lipofuscin accumulation, which were also found in patients with sporadic FTLD‐TDP type A. In contrast, the occipital cortex, a relatively spared brain region in FTD‐GRN, exhibited much milder lysosomal abnormalities. Future studies will assess signs of lysosomal dysfunction in patients with other classes of FTLD pathology to determine whether these changes are limited to patients with FTLD‐TDP or may be found throughout the FTLD spectrum.