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.

• Authors: Skylar E Davis, Anna K Cook, Justin A Hall, Yuliya Voskobiynyk, Nancy V Carullo, Nicholas R Boyle, Ahmad R Hakim, Kristian M Anderson, Kierra P Hobdy, Derian A Pugh, Charles F Murchison, Laura J McMeekin, Micah Simmons, Katherine A Margolies, Rita M Cowell, Alissa L Nana, Salvatore Spina, Lea T Grinberg, Bruce L Miller, William W Seeley, Andrew E Arrant
• Journal: Acta neuropathologica communications (Acta Neuropathol Commun) Vol. 11 Issue 1 Pg. 70 (04 28 2023) ISSN: 2051-5960 [Electronic] England
• PMID: 37118844 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2023. The Author(s).

Chemical References

• lysosomal proteins
• Progranulins
• Cathepsin D
• DNA-Binding Proteins
• Grn protein, mouse

Topics

• Mice
• Animals
• Frontotemporal Dementia (genetics, pathology)
• Pick Disease of the Brain (pathology)
• Progranulins (genetics)
• Cathepsin D (genetics)
• Frontotemporal Lobar Degeneration (pathology)
• Mutation (genetics)
• DNA-Binding Proteins (genetics, metabolism)
• Mice, Transgenic