Single-cell multimodal analysis in a case with reduced penetrance of Progranulin-Frontotemporal Dementia.

Abstract

We identified an autosomal dominant progranulin mutation carrier without symptoms of dementia in her lifetime (Reduced Penetrance Mutation Carrier, RedPenMC). This resistance to develop expected pathology presents a unique opportunity to interrogate neurodegenerative mechanisms. We performed multimodal single-nuclei analyses of post-mortem frontal cortex from RedPenMC, including transcriptomics and global levels of chromatin marks. RedPenMC had an increased ratio of GRN-expressing microglia, higher levels of activating histone mark H3k4me3 in microglia and lower levels of the repressive chromatin marks H3k9me1 and H3k9me3 in the frontal cortex than her affected mutation carrier son and evidence of higher protein levels of progranulin in both plasma and brain homogenates. Although the study is limited to one case, the results support that restoring brain progranulin levels may be sufficient to escape neurodegeneration and FTD. In addition to previously identified modifier genes, it is possible that epigenetic marks may contribute to the increased progranulin expression in cases of reduced penetrance. These findings may stimulate similar follow-up studies and new therapeutic approaches.

• Authors: Karthick Natarajan, Jesper Eisfeldt, Maria Hammond, José Miguel Laffita-Mesa, Kalicharan Patra, Behzad Khoshnood, Linn Öijerstedt, Caroline Graff
• Journal: Acta neuropathologica communications (Acta Neuropathol Commun) Vol. 9 Issue 1 Pg. 132 (08 03 2021) ISSN: 2051-5960 [Electronic] England
• PMID: 34344473 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Chromatin
• Histones
• Progranulins
• histone H3 trimethyl Lys4

Topics

• Aged, 80 and over
• Chromatin (metabolism)
• Female
• Frontal Lobe (metabolism, pathology)
• Frontotemporal Dementia (genetics, metabolism, pathology)
• Gene Expression Profiling
• Heterozygote
• Histones (metabolism)
• Humans
• Microglia (metabolism, pathology)
• Mutation
• Penetrance
• Progranulins (genetics, metabolism)
• Single-Cell Analysis