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

Tomás Lopes da Fonseca, Raquel Pinho, Tiago F Outeiro

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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 (alpha-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 alpha-Syn. We show that this ATP13A2 mutant can enhance a-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.

Original languageEnglish
Pages (from-to)2959-2971
Number of pages13
JournalHuman molecular genetics
Volume25
Issue number14
DOIs
Publication statusPublished - 15 Jul 2016

Keywords

  • NEURONAL CEROID-LIPOFUSCINOSIS
  • KUFOR-RAKEB SYNDROME
  • P-TYPE ATPASE
  • PARKINSONS-DISEASE
  • CATHEPSIN-D
  • IN-VIVO
  • PYRAMIDAL DEGENERATION
  • LYSOSOMAL DYSFUNCTION
  • ER-STRESS
  • ACCUMULATION

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