Sensing α-Synuclein From the Outside via the Prion Protein: Implications for Neurodegeneration

Inês Caldeira Brás, Luísa V. Lopes, Tiago Fleming Outeiro

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Parkinson's disease and other synucleinopathies are characterized by the accumulation of aggregated α-synuclein in intracellular proteinaceous inclusions. The progressive nature of synucleinopathies seems to be related to the cell-to-cell spreading of α-synuclein pathology, and several possible mechanisms have been put forward to explain this phenomenon. In our recent study, we found that α-synuclein oligomers interact with cellular prion protein in glutamatergic synapses. This interaction triggered a signaling cascade involving phosphorylation of Fyn kinase and activation of the N-methyl-d-aspartate receptor, thereby leading to synaptic dysfunction. Here, we present relevant plasma membrane proteins that have been described to interact with α-synuclein and discuss the possible pathological implications. We focus primarily on the prion protein and propose a pathological mechanism in which the interaction between α-synuclein and prion protein leads to the formation of cofilin/actin rods, culminating in long-term potentiation impairment and cognitive dysfunction. We posit that deciphering the mechanisms involved in sensing specific forms of extracellular α-synuclein and transducing this information may prove invaluable in our quest to devise novel diagnostic and therapeutic approaches in PD and other synucleinopathies.

Original languageEnglish
Pages (from-to)1675-1684
Number of pages10
JournalMovement Disorders
Volume33
Issue number11
DOIs
Publication statusPublished - 1 Nov 2018

Keywords

  • Parkinson's disease
  • prion
  • receptor
  • spreading
  • synucleinopathy
  • α-synuclein

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