Expression analysis of Progranulin and TDP‐43 genes in FTLD‐U and FTLD‐MND

Abstract

Mutations in MAPT and Progranulin (PGRN) genes have been found in familial forms of FTLD‐U. MAPT mutations alter tau protein function or isoform ratios and PGRN mutations lead to haploinsufficiency. High PGRN expression was found in central nervous system diseases with microglial activation. PGRN is not present in the TDP‐43 or ubiquitinated inclusions of either familial or sporadic FTLD‐U. There are at least three possibilities regarding the interaction of PGRN and TDP‐43: neurodegeneration may result as a consequence of accumulation of TDP‐43, both may be the result of PGRN mutation, or TDP‐43 accumulation may be protective against neurodegeneration, but ineffective. Our gene expression microarray analysis of homogenates from superficial frontal cortex of post‐mortem frozen FTLD‐U brain showed altered expression of PGRN and TDP‐43 genes. Our array data showed TDP‐43 to be 1.5 fold increased in both FTLD‐MND and FTLD‐U while PGRN showed no gene expression differences between controls and FTLD‐MND. Only one case has a PGRN mutation and whether it is a pathogenic mutation is as yet unknown. Due to high stringency approaches in array analysis it is possible that some disease relevant information is lost. So we further investigated the array results using quantitative Real Time PCR. Preliminary data showed altered expression which will be discussed in detail. Increased PGRN from activated microglia may contribute to artificially normal PGRN.