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... Show moreMutations 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. Clathrin-dependent 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. Show less
Inhabitants of poor, rural areas in the Global South heavily depend on natural resources in their immediate vicinity. Conflicts over and exploitation of these resources - whether it is water, fish... Show moreInhabitants of poor, rural areas in the Global South heavily depend on natural resources in their immediate vicinity. Conflicts over and exploitation of these resources - whether it is water, fish, wood fuel, minerals, or land - severely affect their livelihoods. The contributors to this volume leave behind the polarised debate, previously surrounding the relationship between natural resources and conflict, preferring a more nuanced approach that allows for multiple causes at various levels. The contributions cover a wide array of resources, geographical contexts (Africa, Asia and Latin America), and conflict dynamics. Most are of a comparative nature, exploring experiences of conflict as well as cooperation in multiple regions. This volume finds its origin in an innovative research programme with the acronym CoCooN, steered by The Netherlands Organisation for Scientific Research (NWO/WOTRO) and involving universities and civil society partners in many countries. It presents the conceptual approaches adhered to by each of seven interdisciplinary projects, ranging from green criminology and political ecology to institutional analysis, legal pluralism and identity politics. The volume will be of interest to academics and practitioners concerned with an understanding of conflict as well as cooperation over natural resources. Show less
