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Gain And Loss Of Progranulin Have Opposite Effects On Autophagy

Berlingieri, Stefania (2017). Gain And Loss Of Progranulin Have Opposite Effects On Autophagy. PhD thesis The Open University.

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Abstract

Progranulin (PGRN) is a widely expressed cysteine-rich, secreted glycoprotein with growth factor-like properties. PGRN is involved in both metabolism and neurodegeneration. It has recently emerged as an important regulatory adipokine of glucose metabolism and insulin sensitivity. Individuals with obesity and type 2 diabetes were shown to have increased serum PGRN levels. Heterozygous loss of function mutations in the gene encoding PGRN (GRN) have been described as the major cause of frontotemporal lobar degeneration (FTLD), the most common type of dementia after Alzheimer’s disease (AD), whereas homozygous mutations result in neuronal ceroid lipofuscinosis (NCL), an infantile onset disease. During my Ph.D thesis, I found that hepatic PGRN overexpression in mice results in autophagy impairment leading to metabolic syndrome whereas PGRN loss in mouse brains results in increased activation of autophagy through TNF receptor (TNFR) over-stimulation and C-Jun N-terminal kinase (JNK) activation. Excessive activation of brain autophagy is associated to neurodegeneration and either JNK or autophagy inhibition improve neuronal viability and dysfunction in PGRN deficient neurons and PGRN null C. elegans. Moreover, I found that gain and loss of PGRN have opposite effects on insulin-like growth factor 1 (IGF-1) level, implicated in both metabolism and neurodegenerative disorders. IGF-1 has been linked also to autophagy in several studies. Activation of IGF-1/insulin receptor substrate 2 (IRS-2) signaling, that has been previously demonstrated to activate autophagy, was found in PGRN deficient brain, thus suggesting a role for IGF-1 in the enhanced autophagy associated to neurodegeneration induced by PGRN loss. As stated above, FTLD is the most common form of early-onset dementia, after AD. However, how PGRN loss causes neurodegeneration is not fully understood. These results unravel novel mechanisms involved in neurodegeneration induced by PGRN loss and open new avenues for the investigation of new therapeutic studies in FTDL.

Item Type: Thesis (PhD)
Copyright Holders: 2016 The Author
Keywords: cell death; glycoproteins
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM)
Associated Research Centre: Telethon Institute of Genetics and Medicine
Item ID: 50327
Depositing User: Stefania Berlingieri
Date Deposited: 25 Aug 2017 15:19
Last Modified: 30 Aug 2017 16:33
URI: http://oro.open.ac.uk/id/eprint/50327
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