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Brain progranulin expression in GRN-associated frontotemporal lobar degeneration

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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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Acknowledgments

This work was supported by the National Institutes of Health [K08AG033101-01; AG10124; AG17586; NS44266; AG15116; NS53488], the American Academy of Neurology-ALS Association [Clinician–Scientist Development Award to ACP], and the Burroughs Wellcome Fund [Career Award for Medical Scientists to ACP]. VMYL is the John H. Ware, 3rd, Professor of Alzheimer’s disease research. JQT is the William Maul Measey-Truman G. Schnabel, Jr., Professor of Geriatric Medicine and Gerontology. We thank Theresa Schuck for assistance in immunohistochemical studies. We thank Linda Kwong for helpful advice and discussions. Finally, we thank our patients and their families whose generosity made this work possible.

Conflict of interest statement

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, 3rd Floor Maloney, 3600 Spruce Street, Philadelphia, PA, 19104, USA

    Alice S. Chen-Plotkin, Jiping Xiao, Felix Geser, Maria Martinez-Lage, Travis Unger, Elisabeth M. Wood, Vivianna M. Van Deerlin, John Q. Trojanowski & Virginia M.-Y. Lee

  2. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Alice S. Chen-Plotkin & Murray Grossman

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  1. Alice S. Chen-Plotkin
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Correspondence to Alice S. Chen-Plotkin.

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Chen-Plotkin, A.S., Xiao, J., Geser, F. et al. Brain progranulin expression in GRN-associated frontotemporal lobar degeneration. Acta Neuropathol 119, 111–122 (2010). https://doi.org/10.1007/s00401-009-0576-2

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  • DOI: https://doi.org/10.1007/s00401-009-0576-2

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