Parkinson's disease-associated LRRK2-G2019S mutant acts through regulation of SERCA activity to control ER stress in astrocytes

Acta Neuropathol Commun. 2019 May 2;7(1):68. doi: 10.1186/s40478-019-0716-4.


Accumulating evidence indicates that endoplasmic reticulum (ER) stress is a common feature of Parkinson's disease (PD) and further suggests that several PD-related genes are responsible for ER dysfunction. However, the underlying mechanisms are largely unknown. Here, we defined the mechanism by which LRRK2-G2019S (LRRK2-GS), a pathogenic mutation in the PD-associated gene LRRK2, accelerates ER stress and cell death. Treatment of cells with α-synuclein increased the expression of ER stress proteins and subsequent cell death in LRRK2-GS astrocytes. Intriguingly, we found that LRRK2-GS localizes to the ER membrane, where it interacts with sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and suppress its activity by preventing displacement of phospholamban (PLN). LRRK2-GS-mediated SERCA malfunction leads to ER Ca2+ depletion, which induces the formation of mitochondria-ER contacts and subsequent Ca2+ overload in mitochondria, ultimately resulting in mitochondrial dysfunction. Collectively, our data suggest that, in astrocytes, LRRK2-GS impairs ER Ca2+ homeostasis, which determines cell survival, and as a result, could contribute to the development of PD.

Keywords: Astrocytes; ER stress; LRRK2-G2019S; Mitochondria; Parkinson’s disease; SERCA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Astrocytes / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / metabolism
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / physiology*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Mice, Transgenic
  • Mutation
  • Neurons / metabolism
  • Parkinson Disease / metabolism*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*


  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lrrk2 protein, mouse
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases