Abstract 1559: Progranulin A9D mutation functionally leads to the cytoplasm retardation of angiogenin

Abstract

Abstract Neurodegenerative diseases are progressive neurological disorders with selective neuron loss in particular regions of brain, including frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and many others. Gene defects have been recognized as a prominent factor in the etiology and pathogenesis of neurodegenerative diseases. To date, hundreds of genetic variants that located in dozens of genes have been associated with susceptibility to various neurodegenerative diseases. Among them, more than 60 mutations in progranulin (PGRN) have been reported in FTLD, AD, ALS and PD. One of the mutations in PGRN gene exon 1 introduces a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (PGRN A9D), and results in cytoplasmic mis-sorting of this protein. However, the mechanism of actions of this mis-sorting remains elusive. To address this issue, we first examined the subcellular distribution of PGRN with A9D mutation in human neuronal-like cells (SH-SY5Y). The results have shown that PGRN A9D mutation failed to undergo maturation and accumulated in the stress granules. Interestingly, this mutation also induces redistribution of cellular angiogenin (ANG), a stress response factor and neurodegenerative diseases related protein, from nuclear to cytoplasm. PGRN was also directly interacted with ANG in stress granules. Furthermore, the cytoplasmic retardation of ANG by PGRN A9D mutation abolished ANG-enhanced rRNA transcription and cell survival. Taken together, these results indicate that PGRN with A9D mutation changed localization of ANG as well as cell growth and survival, suggesting that PGRN and ANG act in concert to regulate the progress of neurodegenerative diseases. Citation Format: Jinghao Sheng, Yongdui Chen, Siqi Li, Haojie Dong, Guangdi Chen, Zhengping Xu. Progranulin A9D mutation functionally leads to the cytoplasm retardation of angiogenin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1559. doi:10.1158/1538-7445.AM2015-1559