Patients with sporadic FTLD exhibit similar increases in lysosomal proteins and storage material as patients with FTD due to GRN mutations

Abstract

Loss of function progranulin (GRN) mutations are a major autosomal dominant cause of frontotemporal dementia (FTD). Patients with FTD due to GRN mutations (FTD-GRN) develop frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A) and exhibit elevated levels of lysosomal proteins and storage material in frontal cortex, perhaps indicating lysosomal dysfunction as a mechanism of disease. To investigate whether patients with sporadic FTLD exhibit similar signs of lysosomal dysfunction, we compared lysosomal protein levels, transcript levels, and storage material in patients with FTD-GRN or sporadic FTLD-TDP type A. We analyzed samples from frontal cortex, a degenerated brain region, and occipital cortex, a relatively spared brain region. In frontal cortex, patients with sporadic FTLD-TDP type A exhibited similar increases in lysosomal protein levels, transcript levels, and storage material as patients with FTD-GRN. In occipital cortex of both patient groups, most lysosomal measures did not differ from controls. Frontal cortex from a transgenic mouse model of TDP-opathy had similar increases in cathepsin D and lysosomal storage material, showing that TDP-opathy and neurodegeneration can drive these changes independently of progranulin. To investigate these changes in additional FTLD subtypes, we analyzed frontal cortical samples from patients with sporadic FTLD-TDP type C or Pick’s disease, an FTLD-tau subtype. All sporadic FTLD groups had similar increases in cathepsin D activity, lysosomal membrane proteins, and storage material as FTD-GRN patients. However, patients with FTLD-TDP type C or Pick’s disease did not have similar increases in lysosomal transcripts as patients with FTD-GRN or sporadic FTLD-TDP type A. Based on these data, accumulation of lysosomal proteins and storage material may be a common aspect of end-stage FTLD. However, the unique changes in gene expression in patients with FTD-GRN or sporadic FTLD-TDP type A may indicate distinct underlying lysosomal changes among FTLD subtypes.

Alterations in Lysosomal, Glial and Neurodegenerative Biomarkers in Patients with Sporadic and Genetic Forms of Frontotemporal Dementia

“…PGRN deficiency in lysosomes leads to gangliosidosis, which may contribute to neuroinflammation, and neurodegeneration susceptibility observed in FTLD [ 21 ]. Interestingly, elevated GM2 and GB3 in the brain tissues from sporadic FTD with FTLD-TDP type A pathology suggests that the role of lysosomal dysfunction in neurodegeneration is not limited to GRN mutations [ 16 ]. Albeit the prominent increases of GM2 and GB3 in brain tissues, no significant changes of GM2 were detected in CSF from patients with sporadic FTD or GRN mutation carriers and GB3 levels in CSF is below the detection limit of current assay.…”

“…Lysosomal dysfunction is increasingly recognized as a critical player in the pathogenesis of various neurodegenerative diseases [ 14 , 15 , 16 ]. At a genetic level, mutations in multiple genes related to endolysosomal function have been linked to FTD, including C9orf72, GRN, TARDBP, VCP, CHMP2B, and SQSTM1 [ 17 ].…”