Lipid-dependent deposition of alpha-synuclein and Tau on neuronal Secretogranin II-positive vesicular membranes with age

Sci Rep. 2018 Oct 12;8(1):15207. doi: 10.1038/s41598-018-33474-z.

Abstract

This report demonstrates insoluble alpha-synuclein (aSYN)+ aggregates in human sporadic Parkinson's disease (PD) midbrain that are linearly correlated with loss of glucocerebrosidase (GCase) activity. To identify early protein-lipid interactions that coincide with loss of lipid homeostasis, an aging study was carried out in mice with age-dependent reductions in GCase function. The analysis identified aberrant lipid-association by aSYN and hyperphosphorylated Tau (pTau) in a specific subset of neurotransmitter-containing, Secretogranin II (SgII)+ large, dense-core vesicles (LDCVs) responsible for neurotransmission of dopamine and other monoamines. The lipid vesicle-accumulation was concurrent with loss of PSD-95 suggesting synaptic destabilization. aSYN overexpression in the absence of lipid deregulation did not recapitulate the abnormal association with SgII+ vesicles. These results show lipid-dependent changes occur with age in neuronal vesicular membrane compartments that accumulate lipid-stabilized aSYN and pTau.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Case-Control Studies
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dopaminergic Neurons / metabolism
  • Female
  • Glucosylceramidase / metabolism
  • Humans
  • Lipids / physiology*
  • Male
  • Mice
  • Neurons / metabolism
  • Neurotransmitter Agents / metabolism
  • Parkinson Disease / metabolism
  • Secretogranin II / metabolism*
  • alpha-Synuclein / metabolism*
  • tau Proteins / metabolism*

Substances

  • Lipids
  • Neurotransmitter Agents
  • Secretogranin II
  • alpha-Synuclein
  • tau Proteins
  • Glucosylceramidase
  • Dopamine