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

Mov Disord. 2018 Nov;33(11):1675-1684. doi: 10.1002/mds.27478. Epub 2018 Nov 13.

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. © 2018 International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; prion; receptor; spreading; synucleinopathy; α-synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology*
  • Cognition Disorders / etiology
  • Humans
  • Models, Biological
  • Neurodegenerative Diseases / complications
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology*
  • Prion Proteins / metabolism*
  • Signal Transduction
  • Synapses / metabolism*
  • Synapses / pathology
  • alpha-Synuclein / metabolism*

Substances

  • Prion Proteins
  • alpha-Synuclein