A familial ATP13A2 mutation enhances alpha-synuclein aggregation and promotes cell death.
Aberrant protein-protein interactions are a common pathological hallmark among neurodegenerative diseases, including Parkinson's disease (PD). Thus far, mutations in more than 20 genes have been associated with PD. These genes encode for proteins involved in distinct intracellular pathways, complicating our understanding of the precise molecular mechanisms underlying the disease. Recent reports suggested that the endolysosomal protein ATP13A2 can determine the fate of alpha-synuclein (α-Syn), although no consensus has yet been reached on the mechanisms underlying this effect. Here, we describe, for the first time, the deleterious effect arising from the interaction between the ATP13A2 familial mutant Dup22 with α-Syn. We show that this ATP13A2 mutant can enhance α-Syn oligomerization and aggregation in cell culture. Additionally, we report the accumulation of both proteins in abnormal endoplasmic reticulum membranous structures and the activation of the protein kinase RNA-like endoplasmic reticulum kinase pathway. Ultimately, our data bring new insight into the molecular mechanisms underlying the interplay of these two proteins, opening novel perspectives for therapeutic intervention.
Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen 37073, Germany.|Faculdade de Medicina da Universidade de Lisboa, Lisboa 1648-028, Portugal.
Tomás
T
Lopes da Fonseca
Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen 37073, Germany.|Faculty of Medicine, University of Porto, Porto 4099-002, Portugal.
Raquel
R
Pinho
Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen 37073, Germany touteir@gwdg.de.|CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa 1150, Portugal.|Max Plank Institute for Experimental Medicine, Goettingen 37075, Germany.
Tiago F
TF
Outeiro
D001921:Brain / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000235:genetics; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000235:genetics*; D006180:Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
C514983:ATP13A2 protein, human; D051844:alpha-Synuclein; D006180:Proton-Translocating ATPases