Sequences located within the N-terminus of the PD-linked LRRK2 lead to increased aggregation and attenuation of 6-hydroxydopamine-induced cell death

PLoS One. 2012;7(9):e45149. doi: 10.1371/journal.pone.0045149. Epub 2012 Sep 13.

Abstract

Clinical symptoms of Parkinson's disease (PD) arise from the loss of substantia nigra neurons resulting in bradykinesia, rigidity, and tremor. Intracellular protein aggregates are a pathological hallmark of PD, but whether aggregates contribute to disease progression or represent a protective mechanism remains unknown. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been linked to PD in both familial cases and idiopathic cases and aggregates of the LRRK2 protein are present in postmortem PD brain samples. To determine whether LRRK2 contains a region of protein responsible for self-aggregation, two independent, bioinformatic algorithms were used to identify an N-terminal amino acid sequence as being aggregation-prone. Cells subsequently transfected with a construct containing this domain were found to have significantly increased protein aggregation compared to wild type protein or a construct containing only the last half of the molecule. Finally, in support of the hypothesis that aggregates represent a self-protection strategy, aggregated N-terminal LRRK2 constructs significantly attenuated cell death induced by the PD-mimetic, 6-hydroxydopamine (6-OHDA).

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Amino Acid Sequence
  • Animals
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Humans
  • Mesencephalon / pathology
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism
  • Oxidopamine / toxicity*
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology*
  • Protein Serine-Threonine Kinases / chemistry*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Solubility
  • Structure-Activity Relationship

Substances

  • Oxidopamine
  • Protein Serine-Threonine Kinases