Proteolysis of α-synuclein fibrils in the lysosomal pathway limits induction of inclusion pathology

J Neurochem. 2017 Feb;140(4):662-678. doi: 10.1111/jnc.13743. Epub 2016 Aug 19.


Progression of α-synuclein inclusion pathology may occur through cycles of release and uptake of α-synuclein aggregates, which induce additional intracellular α-synuclein inclusion pathology. This process may explain (i) the presence of α-synuclein inclusion pathology in grafted cells in human brains, and (ii) the slowly progressive nature of most human α-synucleinopathies. It also provides a rationale for therapeutic targeting of extracellular aggregates to limit pathology spread. We investigated the cellular mechanisms underlying intraneuronal α-synuclein aggregation following exposure to exogenous preformed α-synuclein amyloid fibrils. Exogenous α-synuclein fibrils efficiently attached to cell membranes and were subsequently internalized and degraded within the endosomal/lysosomal system. However, internalized α-synuclein amyloid fibrils can apparently overwhelm the endosomal/lysosomal machinery leading to the induction of intraneuronal α-synuclein inclusions comprised of endogenous α-synuclein. Furthermore, the efficiency of inclusion formation was relatively low in these studies compared to studies using primary neuronal-glial cultures over-expressing α-synuclein. Our study indicates that under physiologic conditions, endosomal/lysosomal function acts as an endogenous barrier to the induction of α-synuclein inclusion pathology, but when compromised, it may lower the threshold for pathology induction/transmission. Cover Image for this issue: doi: 10.1111/jnc.13787.

Keywords: Parkinson's disease; degradation; endocytosis; inclusions; lysosome; α-synuclein.

Publication types

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

MeSH terms

  • Amyloid / metabolism*
  • Animals
  • CHO Cells
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Humans
  • Inclusion Bodies / metabolism*
  • Inclusion Bodies / pathology
  • Lysosomes / metabolism*
  • Lysosomes / pathology
  • Mice
  • Mice, Inbred C3H
  • Mice, Knockout
  • Proteolysis*
  • Signal Transduction / physiology*
  • alpha-Synuclein / metabolism*


  • Amyloid
  • alpha-Synuclein