The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease

Bandrés‐Ciga, Sara; Sáez-Atiénzar, Sara; Bonet-Ponce, Luis; Billingsley, Kimberley; Vitale, Dan; Blauwendraat, Cornelis; Gibbs, J. Raphael; Pihlstrøm, Lasse; Gan‐Or, Ziv; Cookson, Mark; Nalls, Mike A.; Singleton, Andrew B.

doi:10.1002/mds.27614

Cited by 72 publications

(72 citation statements)

References 59 publications

(97 reference statements)

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“…46 As such, a significant proportion of PD-heritability is still unaccounted for, likely due to small effect sizes of undiscovered loci that do not surpass GWAS significance thresholds. 61 Here, we used polygenic risk scores to investigate the potential contribution of clathrin-trafficking genes to PD risk. Four genes were present in all PD-associated categories: AP2A1, AP2A2, SNAP91 and PICALM and two of these genes encode for isoforms of the α subunit of the AP2 complex.…”

Section: Discussionmentioning

confidence: 99%

Sequential screening nominates the Parkinson’s disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis

Heaton

Landeck

Mamais

et al. 2020

Preprint

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Mutations in leucine-rich repeat kinase 2 (LRRK2) are an established cause of inherited Parkinson's disease (PD). LRRK2 is expressed in both neurons and glia in the central nervous system, but its physiological function(s) in each of these cell types is uncertain. Through sequential screens, we report a functional interaction between LRRK2 and Clathrin adaptor protein complex 2 (AP2). Analysis of LRRK2 KO tissue revealed a significant dysregulation of AP2 complex components, suggesting LRRK2 may act upstream of AP2. In line with this hypothesis, expression of LRRK2 was found to modify recruitment and phosphorylation of AP2. Furthermore, expression of LRRK2 containing the R1441C pathogenic mutation resulted in impaired clathrin-mediated endocytosis (CME). A decrease in activity-dependent synaptic vesicle endocytosis was also observed in neurons harboring an endogenous R1441C LRRK2 mutation. Alongside LRRK2, several PD-associated genes intersect with membrane-trafficking pathways. To investigate the genetic association between Clathrin-trafficking and PD, we used polygenetic risk profiling from IPDGC genome wide association studies (GWAS) datasets. Clathrindependent endocytosis genes were found to be associated with PD across multiple cohorts, suggesting common variants at these loci represent a cumulative risk factor for disease. Taken together, these findings suggest CME is a LRRK2-mediated, PD relevant pathway.

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Section: Discussionmentioning

confidence: 99%

Sequential screening nominates the Parkinson’s disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis

Heaton

Landeck

Mamais

et al. 2020

Preprint

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“…In addition to the dominantly inherited SNCA and LRRK2 genes, a number of other genes have been linked to PD that are known to act primarily at the synapse; autosomal‐recessive mutations in PRKN , DNAJC6 , and SYNJ1 lead to juvenile onset, atypical forms of PD, and variation at the locus is a PD risk factor . (Fig.…”

Section: Genes Implicated In Pd That Play a Role At The Presynaptic Tmentioning

confidence: 99%

Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

et al. 2019

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While current effective therapies are available for the symptomatic control of PD, treatments to halt the progressive neurodegeneration still do not exist. Loss of dopamine neurons in the SNc and dopamine terminals in the striatum drive the motor features of PD. Multiple lines of research point to several pathways which may contribute to dopaminergic neurodegeneration. These pathways include extensive axonal arborization, mitochondrial dysfunction, dopamine's biochemical properties, abnormal protein accumulation of α‐synuclein, defective autophagy and lysosomal degradation, and synaptic impairment. Thus, understanding the essential features and mechanisms of dopaminergic neuronal vulnerability is a major scientific challenge and highlights an outstanding need for fostering effective therapies against neurodegeneration in PD. This article, which arose from the Movement Disorders 2018 Conference, discusses and reviews the possible mechanisms underlying neuronal vulnerability and potential therapeutic approaches in PD. © 2019 International Parkinson and Movement Disorder Society

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“…Advances in genetics and multiple model systems have revealed an important role of intracellular trafficking defects in Parkinson's disease (PD) (1)(2)(3). Importantly, a recent systematic analysis of pathway-specific genetic risk factors revealed that endocytic membranetrafficking pathway plays a major role in the risk of PD (2).…”

Section: Introductionmentioning

confidence: 99%

LRRK2 regulates AP2M1 phosphorylation cycles to mediate endocytosis and dopaminergic neurodegeneration

Liu

Bautista-Gomez

Higgins

et al. 2020

Preprint

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Recent genetic evidence revealed that endocytic pathway plays a major role in Parkinson's disease (PD) risk. However, the molecular mechanism of how endocytic defects contribute to dopaminergic neurodegeneration in PD is poorly understood. Here we report that LRRK2, the mutations of which are the most genetic causes of PD, binds to and phosphorylates AP2M1, the core component of endocytosis that has been recently implicated in PD risk. Our study revealed that abnormal AP2M1 phosphorylation cycle, regulated either by knockout or overexpression of LRRK2, cause endocytic defects. Our study also uncovered a novel tissuespecific regulation of AP2M1 phosphorylation by LRRK2. Further, we found that LRRK2 phosphorylation on AP2M1 mediates LRRK2-induced neuronal toxicity both in vitro in neuronal cultures and in vivo in Drosophila dopamine neurons. Importantly, AP2M1 phosphorylation levels are elevated in patient fibroblasts of both LRRK2-associated PD and sporadic PD, suggesting the clinical relevance of our finding in PD. Together, our study provides a direct mechanistic link between LRRK2, AP2 and endocytosis in PD pathogenesis.

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The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease

Cited by 72 publications

References 59 publications

Sequential screening nominates the Parkinson’s disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis

Sequential screening nominates the Parkinson’s disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis

Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

LRRK2 regulates AP2M1 phosphorylation cycles to mediate endocytosis and dopaminergic neurodegeneration

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