Brain progranulin expression in GRN -associated frontotemporal lobar degeneration

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ID: 116494
2009
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Abstract
Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is characterized by progressive decline in behavior, executive function, and language. Progranulin (GRN) gene mutations are pathogenic for FTLD-TDP, and GRN transcript haploinsufficiency is the proposed disease mechanism. However, the evidence for this hypothesis comes mainly from blood-derived cells; we measured progranulin expression in brain. We characterized mRNA and protein levels of progranulin from four brain regions (frontal cortex, temporal cortex, occipital cortex, and cerebellum) in FTLD-TDP patients with and without GRN mutations, as well as neurologically normal individuals. Moreover, we performed immunohistochemistry to evaluate the degree of TDP-43 pathology and microglial infiltration present in these groups. In most brain regions, patients with GRN mutations showed mRNA levels comparable to normal controls and to FTLD-TDP without GRN mutations. However, GRN transcript levels in a brain region severely affected by disease (frontal cortex) were increased in mutation-bearing patients. When compared with normal individuals, GRN mutation-bearing cases had a significant reduction in the amount of progranulin protein in the cerebellum and occipital cortex, but not in the frontal and temporal cortices. In GRN mutant cases, GRN mRNA originated from the normal allele, and moderate microglial infiltration was observed. In conclusion, GRN mutation carriers have increased levels of mRNA transcript from the normal allele in brain, and proliferation of microglia likely increases progranulin levels in affected regions of the FTLD-TDP brain, and whether or not these findings underlie the accumulation of TDP-43 pathology in FTLD-TDP linked to GRN mutations remains to be determined.
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chen-plotkin2009actabrain Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Alice S. Chen-Plotkin;Jiping Xiao;Felix Geser;Maria Martinez-Lage;Murray Grossman;Travis Unger;Elisabeth M. Wood;Vivianna M. Van Deerlin;John Q. Trojanowski;Virginia M.-Y. Lee;Alice S. Chen-Plotkin;Jiping Xiao;Felix Geser;Maria Martinez-Lage;Murray Grossman;Travis Unger;Elisabeth M. Wood;Vivianna M. Van Deerlin;John Q. Trojanowski;Virginia M.-Y. Lee;
Journal acta neuropathologica
Year 2009
DOI
doi:10.1007/s00401-009-0576-2
URL
https://link.springer.com/article/10.1007/s00401-009-0576-2
Keywords
pathology neurosciences

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