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Title: Gain and loss of progranulin have opposite effects on autophagy
Author: Berlingieri, Stefania
ISNI:       0000 0004 6424 4215
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2017
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral