Zerillo, Lucrezia (2020) The role of Synj1 in membrane trafficking and its impact in PARK20 pathogenesis. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Resource language: English
Title: The role of Synj1 in membrane trafficking and its impact in PARK20 pathogenesis
Creators:
CreatorsEmail
Zerillo, Lucrezialucrezia.zerillo@unina.it
Date: 13 March 2020
Number of Pages: 95
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Dottorato: Medicina molecolare e biotecnologie mediche
Ciclo di dottorato: 32
Coordinatore del Corso di dottorato:
nomeemail
Avvedimento, Vittorio Enricovittorioenrico.avvedimento@unina.it
Tutor:
nomeemail
Paladino, SimonaUNSPECIFIED
Date: 13 March 2020
Number of Pages: 95
Keywords: Synj1; autophagy; ER stress
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/13 - Biologia applicata
Date Deposited: 25 Mar 2020 11:48
Last Modified: 08 Nov 2021 11:58
URI: http://www.fedoa.unina.it/id/eprint/13172

Collection description

Homeostasis of eukaryotic cells is largely dependent on the dynamic compartmentalization of the endomembrane system. Proper membrane trafficking, which connects different organelles, is essential to maintain the proper composition of cellular compartments as well as to ensure their homeostasis and function. With respect to other cell types, nervous system is more sensitive to alterations of membrane trafficking. In the last years, several genes responsible for hereditary forms of Parkinson’s disease are implicated in regulating membrane trafficking. We have recently highlighted that the alteration of homeostasis and functions of early endosomal compartments is associated with the early-onset parkinsonism (PARK20) caused by R258Q mutation in the phosphoinositide (PI) phosphatase Synaptojanin 1 (Synj1), emphasizing the role of endosomal trafficking in the pathogenesis of Parkinson’s disease. Thanks to two consecutive phosphatase domains, Synj1 dephosphorylates various substrates and for this peculiarity it might play multiple roles; hence defects of Synj1 activity might compromise different intracellular pathways. Main goal of my PhD project was to elucidate the role of Synj1 in membrane trafficking and its impact on PARK20 pathogenesis. Specifically, first aim was to study the role of Synj1 in the secretory pathway since the PI(4)P, which is enriched in the Golgi membranes, is one of Synj1 substrate. Here, we show that the exit machinery from the endoplasmic reticulum (ER) and the ER-to-Golgi trafficking is markedly compromised in PARK20 fibroblasts. As a consequence, they accumulate large amounts of cargo proteins within the ER, leading to the induction of ER stress and, in turn, activation of PERK/eIF2α/ATF4/CHOP pathway of the Unfolded Protein Response (UPR). All together these findings suggest that dysfunction of early secretory pathway might contribute to the pathogenesis of the disease. Second, we studied the role of Synj1 in the autophagy pathway starting from the observation that lysosome structure is altered, despite trafficking toward lysosomes is unaffected, and therefore hypothesizing that these alterations could be due to changes in this process. We observed higher levels of the autophagic markers in Synj1 deficient cells and in PARK20 fibroblasts as well as the increase of the number of autophagosomes. Moreover, autophagic flux results perturbed and the clearance of autophagy substrates was drastically reduced in Synj1-depleted cells. All these data indicate a role of Synj1 in the autophagy pathway from one side, and highlight a potential role of autophagy dysregulation in PARK20 pathogenesis from the other one. Overall, our findings pointed out multiple roles of Synj1 in different cellular pathways. In addition, they highlight that beside the role of endosomal system, defects of early secretory pathway and a dysregulation of autophagy could contribute to PARK20 pathogenesis.

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