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Published on: January 17, 2012
Brain progranulin expression in GRN-associated frontotemporal lobar degeneration
Alice S Chen-Plotkin1, Jiping Xiao, Felix Geser
1Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. chenplot@mail.med.upenn.edu
Acta Neuropathologica
|August 4, 2009
Summary
Progranulin (GRN) gene mutations in frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) do not cause haploinsufficiency in the brain. Microglial proliferation may increase progranulin levels in affected brain regions.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a neurodegenerative disease impacting behavior, executive function, and language.
- Progranulin (GRN) gene mutations are a known cause of FTLD-TDP, with haploinsufficiency of GRN transcript proposed as the disease mechanism.
- Previous evidence for GRN haploinsufficiency primarily derived from blood cells, necessitating brain-specific investigation.
Purpose of the Study:
- To investigate progranulin (GRN) mRNA and protein expression in the brain of FTLD-TDP patients with and without GRN mutations.
- To assess the correlation between GRN expression, TDP-43 pathology, and microglial infiltration in different brain regions.
- To evaluate the validity of the GRN transcript haploinsufficiency hypothesis in the context of FTLD-TDP brain pathology.
Main Methods:
- Quantification of progranulin mRNA and protein levels in four brain regions (frontal cortex, temporal cortex, occipital cortex, cerebellum) from FTLD-TDP patients and controls.
- Immunohistochemical analysis to determine the extent of TDP-43 pathology and microglial infiltration.
- Comparison of GRN expression patterns between patients with GRN mutations, FTLD-TDP without mutations, and neurologically normal individuals.
Main Results:
- GRN mRNA levels were comparable between groups in most brain regions, but increased in the frontal cortex of mutation carriers.
- GRN mutation carriers showed reduced progranulin protein in the cerebellum and occipital cortex, but not frontal or temporal cortices, compared to controls.
- GRN mRNA in mutant cases originated from the normal allele, and moderate microglial infiltration was observed.
Conclusions:
- GRN mutation carriers exhibit increased expression of the normal GRN allele in the brain.
- Microglial proliferation in affected brain regions may contribute to elevated progranulin levels.
- The precise role of these findings in the pathogenesis of TDP-43 accumulation in GRN-linked FTLD-TDP requires further investigation.
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