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A familial ATP13A2 mutation enhances alpha-synuclein aggregation and promotes cell death

Lookup NU author(s): Professor Tiago OuteiroORCiD


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© The Author 2016. 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 alphasynuclein (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.

Publication metadata

Author(s): Fonseca TL, Pinho R, Outeiro TF

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2016

Volume: 25

Issue: 14

Pages: 2959-2971

Print publication date: 15/07/2016

Online publication date: 08/06/2016

Acceptance date: 09/05/2016

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddw147

PubMed id: 27282395


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