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Open Access 01-12-2023 | Frontotemporal Dementia | Research

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

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

Published in: Acta Neuropathologica Communications | Issue 1/2023

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.

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Title: Patients with sporadic FTLD exhibit similar increases in lysosomal proteins and storage material as patients with FTD due to GRN mutations
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
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Frontotemporal Dementia
Frontotemporal Dementia
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01571-4

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

Abstract

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Abstract

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