Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen 37073, Germany
CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa 1150, Portugal
Max Plank Institute for Experimental Medicine, Goettingen 37075, Germany
To whom correspondence should be addressed at: Department of NeuroDegeneration and Restorative Research, University Medical Center Göttingen, Waldweg 33, 37073 Göttingen, Germany. Tel.: +49 (0)5513913544; Fax: +49 (0)5513922693; E-mail: email@example.com
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.