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Monomeric α-synuclein activates the plasma membrane calcium pump.

Antoni Kowalski1,2,3,4, Cristine Betzer2,5, Sigrid Thirup Larsen1,2

  • 1Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.

The EMBO Journal
|November 2, 2023
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Summary

Monomeric alpha-synuclein (aSN) activates plasma membrane calcium ATPase (PMCA) to clear calcium in neurons. This finding reveals a new physiological role for aSN in neuronal calcium homeostasis.

Keywords:
alpha-synucleincalciumcalmodulinplasma membrane Ca2+-ATPasepresynapse

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Cell Biology

Background:

  • Alpha-synuclein (aSN) is intrinsically disordered and linked to neurodegeneration.
  • The physiological role of aSN remains unclear, though it's implicated in protein aggregation.
  • Previous studies suggest aSN interacts with plasma membrane Ca2+-ATPase (PMCA).

Purpose of the Study:

  • To investigate the physiological function of alpha-synuclein (aSN).
  • To determine the interaction between aSN and plasma membrane Ca2+-ATPase (PMCA).
  • To elucidate the role of aSN in neuronal calcium regulation.

Main Methods:

  • Proximity ligation assays to assess aSN and PMCA colocalization.
  • Biochemical assays to measure calcium expulsion activity.
  • Site-mapping on PMCA to identify interaction domains.

Main Results:

  • aSN and PMCA colocalize at neuronal synapses.
  • aSN activates PMCA-mediated calcium expulsion.
  • Monomeric aSN activates PMCA independently of its autoinhibitory domain, dependent on acidic phospholipids and membrane anchoring.
  • The activation site on PMCA is mapped to the acidic lipid-binding site within a disordered loop.

Conclusions:

  • Monomeric aSN acts as a novel stimulator of neuronal calcium clearance.
  • aSN activates PMCA, highlighting a new physiological function in calcium homeostasis.
  • This discovery offers insights into neurodegenerative disease mechanisms potentially linked to calcium dysregulation.