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Synaptic Dysfunction Mediated by Mut...

Nguyen, Maria Bac Ai.

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Synaptic Dysfunction Mediated by Mutant LRRK2 in Parkinson's Disease Pathogenesis.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Synaptic Dysfunction Mediated by Mutant LRRK2 in Parkinson's Disease Pathogenesis./
Author:	Nguyen, Maria Bac Ai.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	106 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-10, Section: B.
Contained By:	Dissertations Abstracts International80-10B.
Subject:	Neurosciences. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13422727
ISBN:	9781392028070

Synaptic Dysfunction Mediated by Mutant LRRK2 in Parkinson's Disease Pathogenesis.
Nguyen, Maria Bac Ai.

Synaptic Dysfunction Mediated by Mutant LRRK2 in Parkinson's Disease Pathogenesis. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 106 p.

Source: Dissertations Abstracts International, Volume: 80-10, Section: B.

Thesis (Ph.D.)--Northwestern University, 2019.

This item must not be sold to any third party vendors.

Identifying key molecular mechanisms and targets for therapeutic development in sporadic neurodegenerative diseases has been challenging. Therefore, in-depth investigation of genetic forms of disease can provide valuable insight into pathogenic disease mechanisms. The discovery of genetic forms of Parkinson's disease (PD) has highlighted the importance of the autophagy/lysosomal and mitochondrial/oxidative stress pathways in disease pathogenesis. However, recently identified PD-linked and risk genes, including DNAJC6 (auxilin), SYNJ1 (synaptojanin 1), and SH3GL2 (endophilin A1), have also highlighted disruptions in synaptic vesicle endocytosis as a significant contributor to disease pathogenesis. Additionally, the roles of other PD genes such as LRRK2, PRKN (parkin), and VPS35 in the regulation of synaptic vesicle endocytosis are beginning to emerge. Here, we will discuss the recent work on the contribution of dysfunctional synaptic vesicle endocytosis to midbrain dopaminergic neurons' selective vulnerability and highlight pathways that mediate the interplay between mitochondrial, lysosomal, and synaptic dysfunction in the pathogenesis of PD. Although defects in synaptic vesicle endocytosis have implicated synaptic dysfunction in PD pathogenesis, how synaptic dysfunction contributes to the vulnerability of human dopaminergic neurons has not been previously explored. We demonstrate that the commonly mutated, PD-linked leucine-rich repeat kinase 2 (LRRK2) mediates the phosphorylation of auxilin in its clathrin-binding domain at position Ser627. Kinase activity-dependent LRRK2 phosphorylation of auxilin led to differential auxilin binding to clathrin resulting in disrupted synaptic vesicle endocytosis and decreased synaptic vesicle density in LRRK2 patient-derived dopaminergic neurons. Moreover, impaired synaptic vesicle endocytosis contributed to the accumulation of oxidized dopamine that in turn mediated pathogenic effects such as decreased glucocerebrosidase activity and increased αSynuclein levels in mutant LRRK2 neurons. Importantly, these pathogenic phenotypes were partially attenuated by restoring wild-type auxilin function in mutant LRRK2 dopaminergic neurons. Together, this work suggests that mutant LRRK2 disrupts synaptic vesicle endocytosis leading to altered dopamine metabolism and dopamine-mediated toxic effects in patient-derived dopaminergic neurons and highlights the importance of synaptic dysfunction in the pathogenesis of Parkinson's disease.

ISBN: 9781392028070Subjects--Topical Terms:

588700
Neurosciences.

Synaptic Dysfunction Mediated by Mutant LRRK2 in Parkinson's Disease Pathogenesis.
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520 $a Identifying key molecular mechanisms and targets for therapeutic development in sporadic neurodegenerative diseases has been challenging. Therefore, in-depth investigation of genetic forms of disease can provide valuable insight into pathogenic disease mechanisms. The discovery of genetic forms of Parkinson's disease (PD) has highlighted the importance of the autophagy/lysosomal and mitochondrial/oxidative stress pathways in disease pathogenesis. However, recently identified PD-linked and risk genes, including DNAJC6 (auxilin), SYNJ1 (synaptojanin 1), and SH3GL2 (endophilin A1), have also highlighted disruptions in synaptic vesicle endocytosis as a significant contributor to disease pathogenesis. Additionally, the roles of other PD genes such as LRRK2, PRKN (parkin), and VPS35 in the regulation of synaptic vesicle endocytosis are beginning to emerge. Here, we will discuss the recent work on the contribution of dysfunctional synaptic vesicle endocytosis to midbrain dopaminergic neurons' selective vulnerability and highlight pathways that mediate the interplay between mitochondrial, lysosomal, and synaptic dysfunction in the pathogenesis of PD. Although defects in synaptic vesicle endocytosis have implicated synaptic dysfunction in PD pathogenesis, how synaptic dysfunction contributes to the vulnerability of human dopaminergic neurons has not been previously explored. We demonstrate that the commonly mutated, PD-linked leucine-rich repeat kinase 2 (LRRK2) mediates the phosphorylation of auxilin in its clathrin-binding domain at position Ser627. Kinase activity-dependent LRRK2 phosphorylation of auxilin led to differential auxilin binding to clathrin resulting in disrupted synaptic vesicle endocytosis and decreased synaptic vesicle density in LRRK2 patient-derived dopaminergic neurons. Moreover, impaired synaptic vesicle endocytosis contributed to the accumulation of oxidized dopamine that in turn mediated pathogenic effects such as decreased glucocerebrosidase activity and increased αSynuclein levels in mutant LRRK2 neurons. Importantly, these pathogenic phenotypes were partially attenuated by restoring wild-type auxilin function in mutant LRRK2 dopaminergic neurons. Together, this work suggests that mutant LRRK2 disrupts synaptic vesicle endocytosis leading to altered dopamine metabolism and dopamine-mediated toxic effects in patient-derived dopaminergic neurons and highlights the importance of synaptic dysfunction in the pathogenesis of Parkinson's disease.
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