Lysosomal trafficking defects link Parkinson’s disease with Gaucher’s disease

Yvette C. Wong, Dimitri Krainc*

*Corresponding author for this work

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Lysosomal dysfunction has been implicated in multiple diseases, including lysosomal storage disorders such as Gaucher's disease, in which loss-of-function mutations in the GBA1 gene encoding the lysosomal hydrolase β-glucocerebrosidase result in lipid substrate accumulation. In Parkinson's disease, α-synuclein accumulates in Lewy bodies and neurites contributing to neuronal death. Previous clinical and genetic evidence has demonstrated an important link between Parkinson's and Gaucher's disease, as GBA1 mutations and variants increase the risk of Parkinson's and Parkinson's patients exhibit decreased β-glucocerebrosidase activity. Using human midbrain neuron cultures, we have found that loss of β-glucocerebrosidase activity promotes α-synuclein accumulation and toxicity, whereas α-synuclein accumulation further contributes to decreased lysosomal β-glucocerebrosidase activity by disrupting β-glucocerebrosidase trafficking to lysosomes. Moreover, α-synuclein accumulation disrupts trafficking of additional lysosomal hydrolases, further contributing to lysosomal dysfunction and neuronal dyshomeostasis. Importantly, promoting β-glucocerebrosidase activity reduces α-synuclein accumulation and rescues lysosomal and neuronal dysfunction, suggesting that β-glucocerebrosidase may be an important therapeutic target for advancing drug discovery in synucleinopathies including Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)1610-1618
Number of pages9
JournalMovement Disorders
Volume31
Issue number11
DOIs
StatePublished - Nov 1 2016

Keywords

  • Gaucher's disease
  • LIMP-2
  • Parkinson's disease
  • α-synuclein
  • β-glucocerebrosidase

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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