ArticleActa neuropathologica communications2023
Patients with sporadic FTLD exhibit similar increases in lysosomal proteins and storage material as patients with FTD due to GRN mutations.
Article in Acta neuropathologica communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 14 citations in OpenAlex.
- Sortilin is Associated with PGRN-Mediated Endoplasmic Reticulum Stress and Activation of Microglia in a Rat Model of Degenerative Cervical Myelopathy.Neuromolecular medicine · 2026Article
- Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia.Neurobiology of disease · 2025Article
- Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia.Molecular neurodegeneration · 2025Article
- Shared and disease-specific pathways in frontotemporal dementia and Alzheimer's and Parkinson's diseases.Nature medicine · 2025Article
- TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency.Scientific reports · 2025Article
- DNA methylation as a contributor to dysregulation of STX6 and other frontotemporal Lobar degeneration genetic risk-associated loci.Acta neuropathologica communications · 2025Article
- Analysis of the splicing landscape of the frontal cortex in FTLD-TDP reveals subtype specific patterns and cryptic splicing.Acta neuropathologica · 2025Article
- DNA methylation as a contributor to dysregulation ofbioRxiv : the preprint server for biology · 2025Article
- Progranulin deficiency in the brain: the interplay between neuronal and non-neuronal cells.Translational neurodegeneration · 2025Review
- Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases?BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Alterations in Lysosomal, Glial and Neurodegenerative Biomarkers in Patients with Sporadic and Genetic Forms of Frontotemporal Dementia.bioRxiv : the preprint server for biology · 2024Article
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21 authors at 3 institutions in 1 country.
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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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